8.4: Innate Immune System - Biology

8.4: Innate Immune System - Biology

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Paper Cut

It’s just a paper cut, but the break in your skin could provide an easy way for pathogens to enter your body. If bacteria were to enter through the cut and infect the wound, your innate immune system would quickly respond with a dizzying array of general defenses.

The innate immune system is a subset of the human immune system that produces rapid but non-specific responses to pathogens. Innate responses are generic rather than tailored to a particular pathogen. Every pathogen that is encountered is responded to in the same general ways by the innate system. Although the innate immune system provides immediate and rapid defenses against pathogens, it does not confer long-lasting immunity to them. In most organisms, the innate immune system is the dominant system of host defense. Other than most vertebrates including humans, the innate immune system is the only system of host defense.

In humans, the innate immune system includes surface barriers, inflammation, the complement system, and a variety of cellular responses. Surface barriers of various types generally keep most pathogens out of the body. If these barriers fail, then other innate defenses are triggered. The triggering event is usually the identification of pathogens by pattern-recognition receptors on cells of the innate immune system. These receptors recognize molecules that are broadly shared by pathogens but distinguishable from host molecules. Alternatively, the other innate defenses may be triggered when damaged, injured, or stressed cells send out alarm signals, many of which are recognized by the same receptors as those that recognize pathogens.

Barriers to Pathogens

The body’s first line of defense consists of three different types of barriers that keep most pathogens out of body tissues. The types of barriers are mechanical, chemical, and biological barriers.

Mechanical Barriers

Mechanical barriers are the first line of defense against pathogens, and they physically block pathogens from entering the body. The skin is the most important mechanical barrier. In fact, it is the single most important defense the body has. The outer layer of skin, the epidermis, is tough and very difficult for pathogens to penetrate. It consists of dead cells that are constantly being shed from the body surface. This helps remove bacteria and other infectious agents that have adhered to the skin. The epidermis also lacks blood vessels and is usually lacking moisture, so it does not provide a suitable environment for most pathogens. Hair, which is an accessory organ of the skin, also helps to keep out pathogens. Hairs inside the nose may trap larger pathogens and other particles in the air before they can enter the airways of the respiratory system.

Mucous membranes provide a mechanical barrier to pathogens and other particles at body openings. These membranes also line the respiratory, gastrointestinal, urinary, and reproductive tracts. Mucous membranes secrete mucus, which is a slimy and somewhat sticky substance that traps pathogens. Many mucous membranes also have hair-like cilia that sweep mucus and trapped pathogens toward body openings where they can be removed from the body. When you sneeze or cough, mucus, and pathogens are mechanically ejected from the nose and throat, as you can see in the photo below. Other mechanical defenses include tears, which wash pathogens from the eyes, and urine, which flushes pathogens out of the urinary tract.

Chemical Barriers

Chemical barriers also protect against infection by pathogens. They destroy pathogens on the outer body surface, at body openings, and on inner body linings. Sweat, mucus, tears, saliva, and breastmilk all contain antimicrobial substances, such as the enzyme lysozyme, that kill pathogens, especially bacteria. Sebaceous glands in the dermis of the skin secrete acids that form a very fine, slightly acidic film on the surface of the skin that acts as a barrier to bacteria, viruses, and other potential contaminants that might penetrate the skin. Urine and vaginal secretions are also too acidic for many pathogens to endure. Semen contains zinc, which most pathogens cannot tolerate, as well as defensins, which are antimicrobial proteins that act mainly by disrupting bacterial cell membranes. In the stomach, stomach acid and digestive enzymes called proteases, which break down proteins, kill most pathogens that enter the gastrointestinal tract in food or water.

Biological Barriers

Biological barriers are living organisms that help protect the body from pathogens. Trillions of harmless bacteria normally live on the human skin and in the urinary, reproductive, and gastrointestinal tracts. These bacteria use up food and surface space that help prevent pathogenic bacteria from colonizing the body. Some of these harmless bacteria also secrete substances that change the conditions of their environment, making it less hospitable to potentially harmful bacteria. For example, they may release toxins or change the pH. All of these effects of harmless bacteria reduce the chances that pathogenic microorganisms will be able to reach sufficient numbers to cause illness.


If pathogens manage to breach the barriers protecting the body, then one of the first active responses of the innate immune system kicks in. This response is inflammation. The main function of inflammation is to establish a physical barrier against the spread of infection. It also eliminates the initial cause of cell injury, clears out dead cells and tissues damaged from the original insult and the inflammatory process, and initiates tissue repair. Inflammation is often a response to infection by pathogens, but there are other possible causes, including burns, frostbite, and exposure to toxins.

The signs and symptoms of inflammation include redness, swelling, warmth, pain, and frequently some loss of function. These symptoms are caused by increased blood flow into infected tissue and a number of other processes, illustrated in Figure (PageIndex{3}) and described below in the text.

Inflammation is triggered by chemicals such as cytokines and histamines, which are released by injured or infected cells or by immune system cells such as macrophages (described in Figure (PageIndex{5})) that are already present in tissues. These chemicals cause capillaries to dilate and become leaky, increasing blood flow to the infected area and allowing blood to enter the tissues. Pathogen-destroying leukocytes, complement proteins, and tissue-repairing proteins migrate into tissue spaces from the bloodstream to attack pathogens and repair their damage. Cytokines also promote chemotaxis, which is migration to the site of infection by leukocytes that destroy pathogens. Some cytokines have anti-viral, antifungal, and antibacterial effects, such as shutting down protein synthesis in host cells, which viruses need in order to survive and replicate.

Complement System

The complement system is a complex biochemical mechanism named for its ability to “complement” the killing of pathogens directly by creating holes in the body of the pathogen and by assisting antibodies. Antibodies are produced as part of an adaptive immune response. The complement system consists of more than two dozen proteins that are normally found in the blood and synthesized in the liver. The proteins usually circulate as non-functional precursor molecules until activated.

Cellular Responses

Cellular responses of the innate immune system involve a variety of different types of leukocytes. Many of these leukocytes circulate in the blood and act like independent, single-celled organisms, searching out and destroying pathogens in the human host. These and other immune cells of the innate system identify pathogens or debris and then help to eliminate them in some way. One way is phagocytosis.


Phagocytosis is an important feature of innate immunity that is performed by cells classified as phagocytes. In the process of phagocytosis, phagocytes engulf and digest pathogens or other harmful particles. Phagocytes generally patrol the body searching for pathogens, but they can also be called to specific locations by the release of cytokines when inflammation occurs. Some phagocytes reside permanently in certain tissues.

As shown in Figure (PageIndex{4}), when a pathogen such as a bacterium is encountered by a phagocyte, the phagocyte extends a portion of its plasma membrane, wrapping the membrane around the pathogen until it is enveloped. Once inside the phagocyte, the pathogen becomes enclosed within an intracellular vesicle called a phagosome. The phagosome then fuses with another vesicle called a lysosome, forming a phagolysosome. Digestive enzymes and acids from the lysosome kill and digest the pathogen in the phagolysosome. The final step of phagocytosis is the excretion of soluble debris from the destroyed pathogen through exocytosis.


Types of leukocytes that kill pathogens by phagocytosis include neutrophils, macrophages, and dendritic cells. Macrophages and dendritic cells are the derivatives of monocytes. Figure (PageIndex{5}) shows five major types of leukocytes, lymphocytes, basophils, eosinophils, neutrophils, and monocytes. Because lymphocytes are mainly involved in the adaptive immune system, they are not discussed in this concept.


Neutrophils are leukocytes that travel throughout the body in the blood and are usually the first immune cells to arrive at the site of an infection. As shown in Figure (PageIndex{5}), these cells contain granules and carry a multilobed nucleus. They are the most numerous types of phagocytes and normally make up at least half of the total circulating leukocytes. The bone marrow of a normal healthy adult produces more than 100 billion neutrophils per day. During acute inflammation, more than 10 times that many neutrophils may be produced each day. Many neutrophils are needed to fight infections because after a neutrophil phagocytizes just a few pathogens, it generally dies.


Macrophages are large phagocytic leukocytes that develop from monocytes. Macrophages spend much of their time within the interstitial fluid in tissues of the body. As shown in Figure (PageIndex{5}), monocytes do not contain granules and carry a big kidney-shaped nucleus. They are the most efficient phagocytes and can phagocytize a substantial number of pathogens or other cells. Macrophages are also versatile cells that produce a wide array of chemicals — including enzymes, complement proteins, and cytokines — in addition to their phagocytic action. As phagocytes, macrophages act as scavengers that rid tissues of worn-out cells and other debris as well as pathogens. In addition, macrophages act as antigen-presenting cells that activate the adaptive immune system. (To learn more about antigen-presenting cells, see the concept Adaptive Immune System.)


Eosinophils are non-phagocytic leukocytes that are related to neutrophils. They specialize in defending against parasites. As shown in Figure (PageIndex{5}), these cells contain granules and carry a bilobed earmuff-shaped nucleus. These leukocytes are very effective in killing large parasites such as worms by secreting a range of highly toxic substances when activated. Eosinophils may become overactive and cause allergies or asthma.


Basophils are non-phagocytic leukocytes that are also related to neutrophils. They are the least numerous of all white blood cells. As shown in Figure (PageIndex{5}), these cells contain granules and carry a bilobed nucleus. Basophils secrete two types of chemicals that aid in body defenses: histamines and heparin. Histamines are responsible for dilating blood vessels and increasing their permeability in inflammation. Heparin inhibits blood clotting and also promotes the movement of leukocytes into an area of infection.

Dendritic Cells

Like macrophages, dendritic cells develop from monocytes (see Figure (PageIndex{6}). They reside in tissues that have contact with the external environment, so they are located mainly in the skin, nose, lungs, stomach, and intestines. Their plasma membrane has extensions. Besides engulfing and digesting pathogens, dendritic cells also act as antigen-presenting cells that trigger adaptive immune responses.

Mast Cells

Mast cells are non-phagocytic leukocytes that help to initiate inflammation by secreting histamines. In some people, histamines trigger allergic reactions as well as inflammation. Mast cells may also secrete chemicals that help defend against parasites.

Natural Killer Cells

Natural killer cells are in the subset of leukocytes called lymphocytes, which are produced by the lymphatic system. Natural killer cells destroy cancerous or virus-infected host cells, although they do not directly attack invading pathogens. Natural killer cells recognize these host cells by a condition they exhibit called “missing self.” Cells with missing self have abnormally low levels of cell-surface proteins of the major histocompatibility complex (MHC), which normally identify body cells as self.


  1. What is the innate immune system?
  2. Identify the body’s first line of defense.
  3. Define and give examples of mechanical and chemical barriers of the innate immune system.
  4. What are biological barriers, and how do they protect the body?
  5. State the purposes of inflammation.
  6. What triggers inflammation, and what signs and symptoms does it cause?
  7. Define the complement system. How does it help destroy pathogens?
  8. List six different types of leukocytes and state their roles in innate immune responses.
  9. Describe two ways that pathogens may evade the innate immune system.
  10. Explain how mucus can contribute to the immune system as both a mechanical barrier and a chemical barrier.
  11. Which type of immune system cell can both phagocytize pathogens and produce chemicals that promote inflammation?

    A. Macrophages

    B. Natural killer cells

    C. Basophils

    D. Mast cells

  12. What are the ways in which phagocytes can encounter pathogens in the body?

  13. Describe different two ways in which enzymes play a role in the innate immune response.

  14. True or False. Complement proteins can be produced by macrophages.

  15. True or False. The main function of inflammation is to secrete repair proteins at the site of damage.

Explore More

Watch this video to learn about the simple power of hand washing:


  1. Oww Papercut by Laurence Facun (Flickr), CC BY 2.0, via Wikimedia Commons
  2. Sneeze by James Gathany; CDC Public Health Image library ID 11162, Public domain via Wikimedia Commons
  3. Inflammatory Response by OpenStax, CC BY 3.0
  4. Phagocytosis by OpenStax, CC BY 3.0
  5. Leukocytes by Suzanne Wakim licensed CC BY 4.0 adapted from:
    • White Blood Cells, CC BY 3.0, staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436.
    • Leukocyte Key by OpenStax College, CC BY 3.0 via Wikimedia Commons
  6. S8-Dendritic Cells Dragging Conidia in Collagen by Judith Behnsen, Priyanka Narang, Mike Hasenberg, Frank Gunzer, Ursula Bilitewski, Nina Klippel, Manfred Rohde, Matthias Brock, Axel A. Brakhage, Matthias Gunzer, CC BY 2.5 via
  7. Text adapted from Human Biology by CK-12 licensed CC BY-NC 3.0

8.4 Nerve Impulses

Figure 8.4.1 Lightning strikes due to a difference in electrical charge, and results in an electrical current.

This amazing cloud-to-surface lightning occurred when a difference in electrical charge built up in a cloud relative to the ground. When the buildup of charge was great enough, a sudden discharge of electricity occurred. A nerve impulse is similar to a lightning strike. Both a nerve impulse and a lightning strike occur because of differences in electrical charge, and both result in an electric current.

All organisms have some type of innate immunity, whether it be a cell membrane, skin or scales, and mucous membranes to keep the non-self separated from the self. Once this barrier is broken, the body mounts an inflammatory response: fever, chemical signals, inflammation. Certain white blood cells produce histamines to cause swelling, call in other types of white blood cells, including neutrophils, which attack invaders and then die, producing pus.

The second line of inflammatory response in the white blood cells’ defense of the organism are phagocytic cells, which are cells that literally engulf and digest other cells, and natural killer cells, which are able to trigger apoptosis to kill body cells infected with viruses or producing tumours.

Sometimes, the innate immune response is overwhelmed by the sheer number of invaders. In these cases, it triggers an increase in body temperature, causing a fever, which makes the invading cells as unhappy as it makes you feel.

Pathogen Recognition

An infection may be intracellular or extracellular, depending on the pathogen. All viruses infect cells and replicate within those cells (intracellularly), whereas bacteria and other parasites may replicate intracellularly or extracellularly, depending on the species. The innate immune system must respond accordingly: by identifying the extracellular pathogen and/or by identifying host cells that have already been infected. When a pathogen enters the body, cells in the blood and lymph detect the specific pathogen-associated molecular patterns (PAMPs) on the pathogen’s surface. PAMPs are carbohydrate, polypeptide, and nucleic acid “signatures” that are expressed by viruses, bacteria, and parasites but which differ from molecules on host cells. The immune system has specific cells, described in [link] and shown in [link], with receptors that recognize these PAMPs. A macrophage is a large phagocytic cell that engulfs foreign particles and pathogens. Macrophages recognize PAMPs via complementary pattern recognition receptors (PRRs) . PRRs are molecules on macrophages and dendritic cells which are in contact with the external environment. A monocyte is a type of white blood cell that circulates in the blood and lymph and differentiates into macrophages after it moves into infected tissue. Dendritic cells bind molecular signatures of pathogens and promote pathogen engulfment and destruction. Toll-like receptors (TLRs) are a type of PRR that recognizes molecules that are shared by pathogens but distinguishable from host molecules). TLRs are present in invertebrates as well as vertebrates, and appear to be one of the most ancient components of the immune system. TLRs have also been identified in the mammalian nervous system.

2-6. The classical pathway is initiated by activation of the C1 complex

The classical pathway plays a role in both innate and adaptive immunity. As we will see in Chapter 9, the first component of this pathway, C1q, links the adaptive humoral immune response to the complement system by binding to antibodies complexed with antigens. C1q can, however, also bind directly to the surface of certain pathogens and thus trigger complement activation in the absence of antibody. C1q is part of the C1 complex, which comprises a single C1q molecule bound to two molecules each of the zymogens C1r and C1s. C1q is a calcium-dependent sugar-binding protein, a lectin, belonging to the collectin family of proteins, which contains both collagen-like and lectin domains hence the name collectin. It has six globular heads, linked together by a collagen-like tail, which surround the (C1r:C1s)2 complex (Fig. 2.10). Binding of more than one of the C1q heads to a pathogen surface causes a conformational change in the (C1r:C1s)2 complex, which leads to activation of an autocatalytic enzymatic activity in C1r the active form of C1r then cleaves its associated C1s to generate an active serine protease.

Figure 2.10

The first protein in the classical pathway of complement activation is C1, which is a complex of C1q, C1r, and C1s. C1q is composed of six identical subunits with globular heads and long collagen-like tails. The tails combine to bind to two molecules each (more. )

Once activated, the C1s enzyme acts on the next two components of the classical pathway, cleaving C4 and then C2 to generate two large fragments, C4b and C2b, which together form the C3 convertase of the classical pathway. In the first step, C1s cleaves C4 to produce C4b, which binds covalently to the surface of the pathogen. The covalently attached C4b then binds one molecule of C2, making it susceptible, in turn, to cleavage by C1s. C1s cleaves C2 to produce the large fragment C2b, which is itself a serine protease. The complex of C4b with the active serine protease C2b remains on the surface of the pathogen as the C3 convertase of the classical pathway. Its most important activity is to cleave large numbers of C3 molecules to produce C3b molecules that coat the pathogen surface. At the same time, the other cleavage product, C3a, initiates a local inflammatory response. These reactions, which comprise the classical pathway of complement activation, are shown in schematic form in Fig. 2.11 the proteins involved, and their active forms, are listed in Fig. 2.12.

Figure 2.11

The classical pathway of complement activation generates a C3 convertase that deposits large numbers of C3b molecules on the pathogen surface. The steps in the reaction are outlined here and detailed in the text. The cleavage of C4 by C1s exposes a reactive (more. )

Figure 2.12

The proteins of the classical pathway of complement activation.

Biology of the Immune System in Animals

Animals are under constant threat of microbial invasion. These potential invaders gain access to the body through the intestine and respiratory tract and the skin. The large and diverse microbiota of the intestine serves to protect the intestine from infectious invaders by occupying a niche that precludes other organisms from establishment there. Other potential invaders are infectious agents spread from other individuals.

To prevent microbial invasion, the body has as part of the innate immune system a series of defenses that collectively constitute a highly effective defense against invasion. These mechanisms include physical barriers such as the skin, which has its own microbiota and utilizes dessication as a mechanism to discourage colonization with other organisms. Inhaled microorganisms and other material are rapidly removed by the mucociliary apparatus, which consists of ciliated epithelial cells and mucus-secreting cells that move inhaled material from the lower to the upper respiratory tract from which they are removed by the cough reflex.

The second line of defense is a “hard-wired” system of innate immunity that depends on a rapid stereotypical response to stop and kill both bacteria and viruses. This is typified by the process of acute inflammation and by the classic illness responses such as a fever.

The third line of defense is the highly complex, specific, and long-lasting adaptive immunity. Because an animal accumulates memory cells after exposure to pathogens, adaptive immunity provides an opportunity for the host to respond to exposure by creating a highly specific and effective response to each individual infectious agent. In the absence of a functional adaptive immune system survival is unlikely.

Pathogens dodge host surveillance

The effectiveness of ETI selects for microbial variants that can avoid NB-LRR-mediated recognition of a particular effector (Fig. 3). Effector allele frequencies are likely to be influenced by their mode of action. The diversity of both flax rust AvrL alleles and oomycete Atr13 and Atr1 alleles suggests one means of effector evolution. These proteins are likely to interact directly in planta with proteins encoded by alleles of the flax L and Arabidopsis RPP1 and RPP13 loci, respectively. The high level of diversifying selection among these effector alleles is presumably selected by host recognition, and hence acts on effector residues that are probably not required for effector function.

A pathogen carries an effector gene (E1) that is recognized by a rare R1 allele (top). This results in selection for an elevated frequency of R1 in the population. Pathogens in which the effector is mutated are then selected, because they can grow on R1-containing plants (right). R1 effectiveness erodes, and, because at least some R genes have associated fitness costs 92 , plants carrying R1 can have reduced fitness (bottom), resulting in reduced R1 frequencies. The pathogen population will still contain individuals with E1. In the absence of R1, E1 will confer increased fitness, and its frequency in the population will increase (left). This will lead to resumption of selection for R1 (top). In populations of plants and pathogens, this cycle is continuously turning, with scores of effectors and many alleles at various R loci in play.

In contrast, effectors providing biochemical functions that generate modifications of host targets are likely to be under purifying selection 85 . NB-LRR activation via recognition of pathogen-induced modified self provides a mechanism for host perception of multiple effectors evolved to compromise the same host target (Fig. 2). For selection to generate an effector that escapes ETI, the effector is likely to lose its nominal function. The simplest pathogen response to host recognition is to jettison the detected effector gene, provided the population’s effector repertoire can cover the potential loss of fitness on susceptible hosts. In fact, effector genes are often associated with mobile genetic elements or telomeres and are commonly observed as presence/absence polymorphisms across bacterial and fungal strains. Indirect recognition of effector action, via recognition of pathogen-induced modified self, is likely to enable relatively stable, durable and evolutionarily economic protection of the set of cellular machinery targeted by pathogen effectors.

ETI can also be overcome through evolution of pathogen effectors that suppress it directly (Fig. 1). For example, in P. syringae pv. phaseolicola, the AvrPphC effector suppresses ETI triggered by the AvrPphF effector in some cultivars of bean, whereas, as its name implies, AvrPphC itself can condition avirulence on different bean cultivars 86 . Other cases of bacterial effectors acting to dampen or inhibit ETI have been observed 38 . Genetic analysis in flax rust revealed so-called inhibitor genes that function to suppress ETI triggered by other avirulence genes 87 . Hence, it seems likely that some effectors suppress the ETI triggered by other effectors.

Microbial evolution in response to ETI may result in two extremes of NB-LRR evolution. NB-LRR gene homologues in diverse Arabidopsis accessions accumulate evolutionary novelty at different rates at different loci 88 . Some NB-LRR genes are not prone to duplication, and are evolving relatively slowly. Their products are perhaps stably associated with a host protein whose integrity they monitor, retarding diversification. Others are evolving more rapidly and may interact directly with rapidly evolving effectors 89,90 . What might drive these evolutionary modes (Fig. 3)? In pathogen populations, the frequency of an effector gene will be enhanced by its ability to promote virulence, and reduced by host recognition. For example, in the flax/flax rust system, avirulence gene frequency in the rust is elevated on plant populations with a lower abundance of the corresponding R genes, consistent with avr genes increasing pathogen fitness 91 . Hence, natural selection should maintain effector function in the absence of recognition. But effector function has a cost that is dependent on the frequency of the corresponding R gene. And R genes may exact a fitness cost in the host 92 . Thus, if effector frequency drops in a pathogen population, hosts might be selected for loss of the corresponding R allele, and the frequency-dependent cycle would continue (Fig. 3).

Systems Biology as Defined by NIH

It used to be as simple as “the knee bone connected to the thigh bone.” Now scientists use systems biology approaches to understand the big picture of how all the pieces interact in an organism. The above illustration depicts an interactome, the whole set of molecular interactions in cells. The interactome is considered an essential systems biology resource.

Ask five different astrophysicists to define a black hole, the saying goes, and you’ll get five different answers. But ask five biomedical researchers to define systems biology, and you’ll get 10 different answers . . . or maybe more.

Systems biology is an approach in biomedical research to understanding the larger picture—be it at the level of the organism, tissue, or cell—by putting its pieces together. It’s in stark contrast to decades of reductionist biology, which involves taking the pieces apart.

Yet with its complicated flow charts that can (in the words of T.S. Eliot) “follow like a tedious argument of insidious intent,” systems biology has scared away more than a few researchers. Still others fail to fully appreciate its usefulness because it lacks a concise, unified definition.

“There [are] an endless number of definitions,” said Ron Germain, chief of NIAID’s new Laboratory of Systems Biology, NIH’s first organized foray into systems biology, which has been nearly a decade in the making. “It’s even worse than the elephant,” that infamous elephant that stymies the attempts of blind men to describe it because each feels just one part.

“Some people think of it as bioinformatics, taking an enormous amount of information and processing it,” Germain said. “The other school of thought thinks of it as computational biology, computing on how the systems work. You need both of these parts.”

The new NIAID lab reflects an intellectual journey that Germain and some of his NIH colleagues embarked upon as the Human Genome Project was nearing completion.

If the NIAID Systems Biology Laboratory were a symphony orchestra, lab chief Ron Germain would be its conductor-musician. As conductor, Germain provides the necessary structure for tempo and harmony. As musician, he provides the immunology base, essentially the study of macrophages. He has recruited "orchestra" members for the lab who have the skills to work on their own but are also able to work together in the name of systems biology.

At that time, circa 2001, biology was rich in genomic data proteomics had come of age and immunologists had identified many cellular and even molecular components of the immune system. Yet predicting immune system behavior remained as elusive as ever.

Whether a systems biology lab could tease out answers was far from clear. But despite the risk, NIAID Director Anthony Fauci and Scientific Director Kathy Zoon committed a steady stream of resources. Together with Germain, they hoped for, and threw their energy into, a new approach to understanding the immune system that would better embrace experimental and computational techniques to explore connections in all their intricate glory.

The new lab, formed in early 2011 from the Program in Systems Immunology and Infectious Disease Modeling (PSIIM), comprises Martin Meier-Schellersheim, head of the Computational Biology Unit Iain Fraser, head of the Signaling Systems Unit Aleksandra Nita-Lazar, head of the Cellular Networks Proteomics Unit John Tsang, head of the Systems Genomics and Bioinformatics Unit and Germain, chief of NIAID’s Lymphocyte Biology Section, providing the immunology base to this operation.

Independently, the unit heads interact with labs at NIH and beyond to establish and incorporate systems biology methods. In true team spirit, they work together to attack the most basic elements of immunology such as a response to an infection or vaccination.

Ironically, to best understand this new lab, we should take a reductionist approach to defining its parts. The system, it seems, is more than the sum of its parts.

Start with Computational Modeling

Sophisticated computational models and simulations represent integral parts of systems biology. In immunology, they are needed to understand the complex biochemical networks that regulate the interactions among the immune system’s cells and between these cells and infectious organisms.

Enter Martin Meier-Schellersheim, a physicist by training. He was the first to join NIAID’s venture in 2001, even before the launch of PSIIM. He has been most successful in empowering non–computational biologists to do computational biology. Indeed, he has helped foster the very team concept that underlies the new lab his software brings advanced computational capacity to a broad range of biologists.

This willing involvement of biologists is paramount because models need solid experimental data as input and as a reference to ensure reality checks. Otherwise the biological models are likely to be oversimplified either for lack of data or because their development suffers from poor communication between experimentalists and theorists.

Meier-Schellersheim’s primary software tool, called Simmune, facilitates the construction and simulation of realistic multiscale biological processes. He is also involved in the ongoing development of a systems biology markup language, SBML3, that can encode advanced models of cellular signaling pathways.

Add Some Cell Biology

Iain Fraser, a biochemist and molecular biologist interested in the mechanisms of cell signaling, arrived at NIH in 2008. As the lead high-throughput member of the lab, he has several powerful tools on hand to generate key data sets. These data sets ultimately feed into Meier-Schellersheim’s software to produce quantitative models.

Fraser’s tools include in-house genome-wide RNAi screens to characterize signaling network relationships in hematopoietic cells. Such screens are beginning to identify key components in innate immune pathogen-sensing networks. He interacts closely with the NIH-wide RNAi screening group at the NIH Chemical Genomics Center and also with the RNAi Global consortium.

Fraser said immune-system signaling networks can be unraveled by using proper systematic approaches to interpret complex data sets. He offers the example of Toll-like receptors (TLRs), which trigger an intricate cellular response that activates multiple intracellular signaling pathways.

Excessive activation can lead to chronic inflammatory disorders insufficient activation can render the host susceptible to infection. Unbiased screening approaches can help identify the components that allow the immune system to maintain a homeostatic balance in the face of microbial challenges.

One of Fraser’s early successes, using a systems biology approach, was demonstrating how a single protein kinase can mediate the anti-inflammatory effects of cyclic adenosine monophosphate in its crosstalk with TLR4.

Fraser sums up his time at NIH as establishing “the screening infrastructure for dissecting the response of the macrophage to a broad range of pathogenic stimuli.”

The “orchestra” members for NIAID’s new Systems Biology Laboratory include (clockwise from top left) Martin Meier-Schellersheim, head of the Computational Biology Unit Iain Fraser, head of the Signaling Systems Unit Aleksandra Nita-Lazar, head of the Cellular Networks Proteomics Unit and John Tsang, head of the Systems Genomics and Bioinformatics Unit.

One Generous Serving of Proteomics

Aleksandra Nita-Lazar is developing new methods to obtain quantitative data that improve our understanding of cell biology and also funnel key information into model building. Her domain is the system-wide analysis of the proteome, which has fallen behind DNA analysis partly for want of the necessary tools.

The difference stems from the accommodating nature of DNA. DNA is easily recognized, replicable, and relatively stable, whereas the folded structure of proteins can’t be amplified. Yet protein studies are essential in developing useful models for many reasons, Nita-Lazar said. Such studies can reveal the molecular constituents of a cell provide information about the biochemical state of the proteins and determine catalytic rates and the association and disassociation rates for molecular pairs.

Nita-Lazar uses mass spectrometry to investigate protein phosphorylation, the process of binding with a phosphate group, one of the most common modes of protein-function regulation. She can use the same protocols that Fraser helped develop, and the same cell types, to determine which proteins are phosphorylated in response to a particular stimulus, when they are phosphorylated, and how those data fit into what is known about the transcriptional response.

Nita-Lazar’s group, with Fraser’s group, has been harvesting from these screens the key components required for the signal to flow through a pathway and also for the induction of the inflammatory cytokine messenger RNAs that arise. “This kind of approach used to be dismissed as a fishing expedition,” said Nita-Lazar. The goal is not to catch that one big tuna, however nice that would be, but rather to see the whole school of fish, the entire ecosystem.

Mix Well with Genomics

The enormous amount of data being collected requires processing and analysis—computational tools plus genetics and genomics “to build things from the top down,” Germain said.

Enter John Tsang, the most recent member of Germain’s lab and the element that transformed the PSIIM into a full-fledged systems biology lab.

On the genomics side, Tsang collects and analyzes data on gene expression, miRNAs, epigenetic modifications, and commensal microbes, and he conducts experiments to connect signaling to gene expression. On the bioinformatics side, he develops and applies statistical tools for large and diverse data sets, such as data from microarrays and high-throughput screenings, with an eye toward network models that involve genes, proteins, miRNAs, and epigenetic states.

Tsang also heads bioinformatics at the trans-NIH Center for Human Immunology (CHI), using similar integrative genomics approaches to study the human immune system, such as immune reactions to the flu vaccine in patients.

A core theme for building network models is capitalizing on systematic perturbations and -omics technologies to measure genome-wide responses. From the TLR stimulations that Fraser studies to vaccinations and natural genetic variations in humans, “all are valuable perturbations to help us figure out the wiring and function of the underlying system,” said Tsang.

Oh, Right, Immunology Too

“So, what am I doing in all of this aside from raising money and pontificating?” Germain joked.

If the NIAID Systems Biology Laboratory could be considered a symphony orchestra, Germain would be its conductor-musician. As conductor, he provides the necessary structure for tempo and harmony. As the musician, he provides the immunology base, essentially the study of macrophages.

Germain has seen systems biology labs in which collaborations are more opportunistic than routine, the shortsighted result of building a building, adding smart people, and hoping it all works out. His strategy instead has been to recruit individuals with the necessary skill sets to work on their own but also to work together in the name of systems biology.

“We all have slightly different interests, but there is enough overlap between those interests for us to develop those core projects and for us to be invested in them,” said Fraser.

Don W. Fawcett, Emma Shelton

Macrophages and lymphocytes, the two types of immune cells pictured above, interact with their surroundings in complicated ways. NIH researchers are using systems biology approaches to understand the totality of such interactions.

All Together Now

To understand the response to infection or vaccination at an integrated level, the lab is studying the intersection of innate and adaptive receptor-dependent pathways and their control of gene networks. The researchers have bottom-up projects to understand and model the signaling within specific cell types at a fine-grained level.

And they have a top-down approach that uses inferences from perturbation analyses to probe the large-scale structure of the interactions not only at the cellular level, but also at the tissue and even the organism level.

To accomplish this grand goal, Germain said, the lab works in digestible chunks, focusing on pathogen sensing in key innate cells, such as macrophages, and the intersection of signaling by antigen receptors, cytokines, and TLRs in determining whether B cells become memory cells or long-lived plasma cells.

This process is critical for vaccine development. At the top-down level, the lab uses host genetics and microbiota variation to explore how the immune system’s set point is determined for responses to infections and vaccines.

This early into the chase, the lab has not yet published results on these pursuits, although a paper is pending on the lab’s work with CHI and the flu.

Towards a Trans-NIH Approach

Germain hopes the Laboratory of Systems Biology will serve “as an intellectual resource for people who are thinking in the systems mode and have their hands on these technologies [and want] to see how they could be applied to their work.”

He named the lab the Laboratory of Systems Biology with no mention of immunology or host-pathogen interaction to designate its raison d’être. Inspired by NIAID’s efforts, NCI and NHLBI are actively recruiting researchers to establish systems biology programs. NHLBI has just named Keji Zhao, senior investigator, as director of its new Systems Biology Center.

Meanwhile, the trans-NIH effort for a Center for Systems Biology is not dead. A search for a very senior systems biologist to develop and lead the center came up dry, and now the budgetary stresses have put the search on hold. But most NIH researchers understand that purely reductionist approaches to biology are no longer enough to solve complex biological problems and that integrated approaches are needed. David Levens (NCI), Dan Camerini (NIDDK), and Alan Michelson (NHLBI), along with Germain, continue to lead efforts for this trans-NIH initiative.

NIAID’s Laboratory of Systems Biology is “a smaller model of what the larger enterprise could be,” Germain said. The new lab “is very good for the NIH. We are getting applicants from top universities who want to come to the lab as fellows.”

And the NIH intramural research program is well suited for systems biology, with a long-term perspective and a retrospective review process that doesn’t require grant writing.

Germain helped change the NIH tenure process, too, to be sure that team science, and not necessarily a steady stream of published papers, is recognized and rewarded.

“Nothing happens if you don’t put work into it,” he added.

Reporter’s note:

Ron Germain does have his own definition of systems biology that he’s sticking to: a scientific approach that combines the principles of engineering, mathematics, physics, and computer science with extensive experimental data to develop a quantitative as well as a deep conceptual understanding of biological phenomena, permitting prediction and accurate simulation of complex (emergent) biological behaviors.

System Biology of Inflammation & Innate Immunity

To permit improved understanding of the massively complex innate immune (inflammatory) network and to understand the basis for activity of our immunomodulatory peptides, the Hancock Lab with its collaborators have developed, validated and established highly powerful bioinformatics tools for understanding high throughput genomics datasets.

Our major data source is RNA-Seq which we perform in house yielding a massive amount of transcriptomic data. To interpret this data through mapping to protein:protein interaction networks, with funding from the Grand Challenges in Global Health Research Program, Genome Canada and Canadian Institutes for Health Research, we developed and validated large databases (InnateDB, NetworkAnalyst) with integrated, sophisticated analysis tools, made them freely available to other researchers as open-source tools, and applied them to generate advanced understanding of host responses to pathogens and inflammatory diseases (see Link for general strategies). InnateDB, is an open-source, publicly-available database and systems biology analysis platform of all the genes, proteins, experimentally validated molecular interactions, and pathways in the human, mouse and bovine innate immune responses. It has become an important tool in immunology with

6 million hits per year, from

12,000 distinct internet addresses. Our newest tool is the NetworkAnalyst platform recently published in Nature Protocols, and featuring statistical, visual and network-based approaches for meta-analysis and systems-level interpretation of transcriptomic, proteomic, and metabolomics data. By coupling the latest methods in network biology with cutting-edge visual analytics technologies, it delivers extremely fast network layout, hub analysis and visualization. It enables unbiased examination of large transcriptome datasets as networks based on known protein-protein interactions. Mining of the information for sub-networks, hubs and pathways permits unique insights into data including differences due to specific mutations, experimental conditions and stimuli.

Interaction Network for host transcriptional responses in whole lungs from mice infected with Pseudomonas aeruginosa PA103 vs. control.

Collectively these tools and strategies are enabling exciting new insights into infections and inflammatory diseases. For example, in cystic fibrosis, systems biology studies provided tremendous mechanistic insights into excessive inflammatory responses, and three novel approaches to therapy of hyperinflammatory lung disease in these patients whereas in sepsis use of these tools enabled us to identify a signature of cellular reprogramming/endotoxin tolerance, present in more than 600 diverse patients as early as the emergency ward, predicted the onset of severe sepsis and organ failure (p<0.001 to p<10-6 AUC 98%). We are also studying large datasets on (1) retinoic acid supplement in oral vaccine efficacy in man, (2) investigating the systems biology of infections, (3) mouse sepsis and treatment with BCG, (4) determining the basis for efficacy of vaccines in early life in the Neonatal Vaccination Project, (5) studying the systems biology of mycobacterial disease of cattle and using this to pursue reverse vaccinology approaches to make effective subunit vaccines, (6) studying the impact of rhinovirus on epithelial cells for individuals with cystic fibrosis, and (7) deciphering the basis of wound healing defects in asthma patients. In our hands bioinformatics using network biology approaches is an excellent method for deriving new hypotheses for subsequent lab testing.

More recently we have been exploring how to integrate patient metadata with transcriptomic data enabling the correlation of particular metadata parameters (e.g., gender, clinical symptoms or test results, disease status, treatments, etc) with transcriptomics using as one of our major tools the open source R statistical computer language based FactomineR. We have performed this extensively for infants with the rare blood vessel inflammatory disease syndrome, vasculitis, (manuscript in preparation) and this has allowed us to classify patients with previously unclassified vasculitis (UCV in Fig. 1), but also to discriminate between two forms of small blood vessel inflammatory diseases that physicians struggle to differentiate, namely Microscopic Polyangitis (MPA) and Granulomatosis with Polyangitis (GPA).

With the Wellcome Trust Sanger Institute, we are engaged in a large project to phenotype homozygous knockout mutants of mouse and human stems cells. In particular we are investigating (1) Chlamydia infections of human induced pluripotent stem cell derived macrophages and derived homozygous mutants, and (2) the influence of gene knockouts and immune stimuli on mouse embryonic stem cell derived macrophages.

Amplifying our ancient immune system could help fight future pandemics

FOR immunologists, the covid-19 pandemic has been a steep learning curve. “We’ve learned much more about the host immune response to SARS-CoV-2 in a matter of a few months than we have about many, many other viruses that we’ve dealt with for decades,” says Bali Pulendran at Stanford University in California. At every turn, the virus has confounded expectations, from why it leaves some people unscathed but kills others in days to the “cytokine storms” that wrack the bodies of those who become seriously ill. And then there was the nail-biting wait to see if vaccines were possible. But one discovery above all will have immunologists rewriting their textbooks.

This concerns a long-neglected backwater of the immune system called innate immunity. Once seen as a rather prosaic and primitive bit of human biology, it now turns out to play a pivotal, and often decisive, role in the body’s reaction to SARS-CoV-2 and the vaccines against the virus. And not just that: a better appreciation of it is also being touted as our best bet for seeing off the next pandemic.

Being vertebrates, we are the proud owners of two immune systems (see “Meet your immune system”). One is the “adaptive” system, a smart and highly effective special force that develops and deploys precision weapons against invaders. This is the now-familiar arsenal of antibodies and T-cells that have been such a focus of interest during the pandemic. It is often what people mean when they talk about “the” immune system. But it is only half of the story.

The other half is the innate immune system, which is much less &hellip

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Watch the video: Antiviral Innate Immunity part 1 20211014 (August 2022).