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Infection Immunity


Introduction

The development of an infectious disease in an individual involves complex interactions between the microbe and the host. The key events during infection include entry of the microbe, invasion and colonization of host tissues, evasion of host immunity, and tissue injury or functional impairment. Microbes produce disease by directly killing the host cells they infect, or by liberating toxins that can cause tissue damage and functional derangements in neighboring or distant cells and tissues that are not infected.

The interaction of the immune system with infectious organisms is a dynamic interplay of host mechanisms aimed at eliminating infections and microbial strategies designed to permit survival in the face of powerful defenses. Different types of infectious agents stimulate distinct types of immune responses and have evolved unique mechanisms for evading immunity. In some infections, the immune response is the cause of tissue injury and disease.

Here we will consider the main features of immunity to four major categories of pathogenic microorganisms: extracellular and intracellular bacteria, fungi, viruses, and protozoan as well as multicellular parasites.

Immunity to Bacteria

1)Extracellular Bacteria

Extracellular bacteria are capable of replicating outside host cells, for example, in the blood, in connective tissues, and in tissue spaces such as the lumens of the airways and gastrointestinal tract. Many different species of extracellular bacteria are pathogenic, and disease is caused by two principal mechanisms. First, these bacteria induce inflammation, which results in tissue destruction at the site of infection. Second, bacteria produce toxins, which have diverse pathologic effects. The toxins may be endotoxins, which are components of bacterial cell walls, or exotoxins, which are secreted by the bacteria. The endotoxin of gram-negative bacteria, also called lipopolysaccharide (LPS), is a potent activator of macrophages, dendritic cells, and endothelial cells. Many exotoxins are cytotoxic, and others cause disease by various mechanisms. For instance, diphtheria toxin shuts down protein synthesis in infected cells, cholera toxin interferes with ion and water transport, tetanus toxin inhibits neuromuscular transmission, and anthrax toxin disrupts several critical biochemical signaling pathways in infected cells. Other exotoxins interfere with normal cellular functions without killing cells, and yet other exotoxins stimulate the production of cytokines that cause disease.

a.Innate Immunity

The principal mechanisms of innate immunity to extracellular bacteria are complement activation, phagocytosis, and the inflammatory response.

Complement activation: Peptidoglycans in the cell walls of Gram-positive bacteria and LPS in Gram-negative bacteria activate complement by the alternative pathway. Bacteria that express mannose on their surface may bind mannose-binding lectin, which activates complement by the lectin pathway. One result of complement activation is opsonization and enhanced phagocytosis of the bacteria. In addition, the membrane attack complex generated by complement activation lyses bacteria, Phagocytes and inflammation: Phagocytes (neutrophils and macrophages) use surface receptors, including mannose receptors and scavenger receptors, to recognize extracellular bacteria, and they use Fc receptors and complement receptors to recognize bacteria opsonized with antibodies and complement proteins, respectively. In addition, dendritic cells and phagocytes that are activated by the microbes secrete cytokines, which induce leukocyte infiltration into sites of infection (inflammation). The recruited leukocytes ingest and destroy the bacteria.

b.Adaptive Immunity

Humoral immunity is a major protective immune response against extracellular bacteria, and it functions to block infection, to eliminate the microbes, and to neutralize their toxins. Antibody responses against extracellular bacteria are directed against cell wall antigens and secreted and cell-associated toxins, which may be polysaccharides or proteins. The polysaccharides are prototypic T-independent antigens, and humoral immunity is the principal mechanism of defense against polysaccharide-rich encapsulated bacteria. The effector mechanisms used by antibodies to combat these infections include neutralization, opsonization and phagocytosis, and activation of complement by the classical pathway. The protein antigens of extracellular bacteria also activate CD4+ helper T cells, which produce cytokines that induce local inflammation, enhance the phagocytic and microbicidal activities of macrophages and neutrophils, and stimulate antibody production. (Figure 1)

Adaptive immune responses to extracellular microbes

Figure 1. Adaptive immune responses to extracellular microbes. Adaptive immune responses to extracellular microbes such as bacteria and their toxins consist of antibody production and the activation of CD4+ helper T cells.

2)Intracellular Bacteria

A characteristic of facultative intracellular bacteria is their ability to survive and even to replicate within phagocytes. Because these microbes are able to find a niche where they are inaccessible to circulating antibodies, their elimination requires the mechanisms of cell-mediated immunity.

a.Innate Immunity

The innate immune response to intracellular bacteria is mediated mainly by phagocytes and natural killer (NK) cells. Intracellular bacteria activate NK cells by inducing expression of NK cell–activating ligands on infected cells and by stimulating dendritic cell and macrophage production of IL-12 and IL-15, both of which are NK cell activating cytokines. The NK cells produce IFN-γ, which in turn activates macrophages and promotes killing of the phagocytosed bacteria. Thus, the NK cells provide an early defense against these microbes, before the development of adaptive immunity. (Figure 2a)

b.Adaptive Immunity

The major protective immune response against intracellular bacteria is T cell–mediated recruitment and activation of phagocytes (cell-mediated immunity). Phagocytosed bacteria stimulate CD8+ T cell responses if bacterial antigens are transported from phagosomes into the cytosol or if the bacteria escape from phagosomes and enter the cytoplasm of infected cells. In the cytosol, the microbes are no longer susceptible to the microbicidal mechanisms of phagocytes, and for eradication of the infection, the infected cells have to be killed by CTLs. Thus, the effectors of cell-mediated immunity, namely, CD4+ T cells that activate macrophages and CD8+ CTLs, function cooperatively in defense against intracellular bacteria. (Figure 2b)

Innate and adaptive immunity to intracellular bacteria

Figure 2 Innate and adaptive immunity to intracellular bacteria.

Immunity to Virus

Viruses are obligatory intracellular microorganisms that use components of the nucleic acid and protein synthetic machinery of the host to replicate and spread. Viruses typically infect various cell types by using normal cell surface molecules as receptors to enter the cells. After entering cells, viruses can cause tissue injury and disease by any of several mechanisms. Innate and adaptive immune responses to viruses are aimed at blocking infection and eliminating infected cells. Infection is prevented by type I interferons as part of innate immunity and neutralizing antibodies contributing to adaptive immunity. Once infection is established, infected cells are eliminated by NK cells in the innate response and CTLs in the adaptive response.

1)Innate Immunity to Virus

The principal mechanisms of innate immunity against viruses are inhibition of infection by type I interferons and NK cell–mediated killing of infected cells. NK cells kill other cells infected with a variety of viruses and are an important mechanism of immunity against viruses early in the course of infection, before adaptive immune responses have developed (Figure 3a).

2)Adapted Immunity to Virus

Adaptive immunity against viral infections is mediated by antibodies, which block virus binding and entry into host cells, and by CTLs, which eliminate the infection by killing infected cells. Antibodies are effective against viruses only during the extracellular stage of the lives of these microbes. Viruses may be extracellular early in the course of infection, before they infect host cells, or when they are released from infected cells by virus budding or if the infected cells die. Antiviral antibodies bind to viral envelope or capsid antigens and function mainly as neutralizing antibodies to prevent virus attachment and entry into host cells. Elimination of viruses that reside within cells is mediated by CTLs, which kill the infected cells. The principal physiologic function of CTLs is surveillance against viral infection. Most virus-specific CTLs are CD8+ T cells that recognize cytosolic, usually endogenously synthesized, viral peptides presented by class I MHC molecules (Figure 3b).

Innate and adaptive immune responses against viruses

Figure 3. Innate and adaptive immune responses against viruses.

Immunity to Parasites

In infectious disease terminology, parasitic infection refers to infection with animal parasites such as protozoa, helminths, and ectoparasites (e.g., ticks and mites). Most parasites go through complex life cycles, part of which occurs in humans (or other vertebrates) and part of which occurs in intermediate hosts, such as flies, ticks, and snails. Humans are usually infected by bites from infected intermediate hosts or by sharing a particular habitat with an intermediate host. Most parasitic infections are chronic because of weak innate immunity and the ability of parasites to evade or resist elimination by adaptive immune responses. Furthermore, many anti-parasitic drugs are not effective at killing the organisms.

1)Innate Immunity to Parasites

Although different protozoan and helminthic parasites have been shown to activate different mechanisms of innate immunity, these organisms are often able to survive and replicate in their hosts because they are well adapted to resist host defenses. The principal innate immune response to protozoa is phagocytosis, but many of these parasites are resistant to phagocytic killing and may even replicate within macrophages. Phagocytes may also attack helminthic parasites and secrete microbicidal substances to kill organisms that are too large to be phagocytosed. However, many helminths have thick teguments that make them resistant to the cytocidal mechanisms of neutrophils and macrophages, and they are too large to be ingested by phagocytes.

2)Adapted Immunity to Parasites

Different protozoa and helminths vary greatly in their structural and biochemical properties, life cycles, and pathogenic mechanisms. It is therefore not surprising that different parasites elicit distinct adaptive immune responses. Some pathogenic protozoa have evolved to survive within host cells, so protective immunity against these organisms is mediated by mechanisms similar to those that eliminate intracellular bacteria and viruses. In contrast, metazoa such as helminths to survive in extracellular tissues, and their elimination is often dependent on special types of antibody responses. The principal defense mechanism against protozoa that survive within macrophages is cell-mediated immunity, particularly macrophage activation by TH1 cell–derived cytokines. Defense against many helminthic infections is mediated by the activation of TH2 cells, which result in production of IgE antibodies and activation of eosinophils.

Immunity to Fungus

Fungal infections, also called mycoses, are important causes of morbidity and mortality in humans. Some fungal infections are endemic, and these infections are usually caused by fungi that are present in the environment and whose spores enter humans. Other fungal infections are said to be opportunistic because the causative agents cause mild or no disease in healthy individuals but may infect and cause severe disease in immunodeficient persons. Compromised immunity is the most important predisposing factor for clinically significant fungal infections. Different fungi infect humans and may live in extracellular tissues and within phagocytes. Therefore, the immune responses to these microbes are often combinations of the responses to extracellular and intracellular bacteria. However, less is known about antifungal immunity than about immunity against bacteria and viruses.

Detection and Diagnosis of Infectious Diseases

Infectious diseases are caused by pathogenic microorganisms, such as bacteria, viruses, parasites or fungi. Some infectious diseases can be passed from person to person. Some are transmitted by bites of insects or animals. And others are acquired by ingesting contaminated food or water or being exposed to organisms in the environment. Infectious diseases resulted in about 9 million deaths every year. The symptoms of infection depend on the type of disease. Some signs of infection affect the whole body generally, such as fatigue, loss of appetite, weight loss, fevers, night sweats, chills, aches and pains. Others are specific to individual body parts, such as skin rashes, coughing, or a runny nose. Source organism diagnosis and detection of infectious disease is the key to its prevention and treatment.

Diagnosis of infectious disease sometimes involves identifying an infectious agent either directly or indirectly. Microscopy and microbial culture is probably the most direct method and the golden standard to identify the cause organism of an infectious disease, but it usually needs days or weeks before the results available. Furthermore, not all pathogens can be cultured, that make indirectly method very useful in diagnostic and detection of infectious disease.

Both nucleic acid and proteins as well as small molecular chemicals can be used to detect pathogens. Nucleic acid as genetic material is ubiquity within all kinds of pathogens that make it an ideal marker of pathogen detection and identification. Proteins as the structure and functional material of microbial is also important for diagnostic and detection. Cell wall and pili of bacterial, capsid of the virus, spores of the fungus, surface antigen of parasites and even the metabolic product of these pathogen are all biomarkers for diagnosis and detection of infectious disease (Figure 4).

Pathogens and Virulence factors of infectious diseases

Figure 4. Pathogenic factors of infectious diseases.

Divers biotechnology or immunoassay such as PCR (detect nucleic acid), ELISA (detect pathogenic antigen or antibody) are widely applied in this area. Many of them are commercialized products. Creative diagnostic offers a wide variety of enzyme-linked immunosorbent assay (ELISA) kits, Rapid diagnostic kits as well as the related antigens and antibodies for the diagnostic and detection of infectious disease.

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Reference:

1. Murphy K M. Janeway's immunobiology[M]. Garland Science, 2011.
2. Abbas A K, Lichtman A H H, Pillai S. Cellular and Molecular Immunology: with STUDENT CONSULT Online Access[M]. Elsevier Health Sciences, 2014.

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