Lecture 30: Immunity to Infection (Kaushik 2024) PDF

Chapter 13: Immunity to infection.  Lecture outline Immunity to Infection Immunity to Viruses Viral Evasion Strategies Immunity to Protozoa Immunity to Helminths and Parasites Immunity to Fungi Immunity to Prions  Immunity to viruses: Disease mechanisms Viruses...

Chapter 13: Immunity to infection.  Lecture outline Immunity to Infection Immunity to Viruses Viral Evasion Strategies Immunity to Protozoa Immunity to Helminths and Parasites Immunity to Fungi Immunity to Prions  Immunity to viruses: Disease mechanisms Viruses are intracellular pathogens that consist of a nucleic acid genome packaged in a protein coat called a capsid. Genome may be DNA or RNA, & capsid may or may not be covered with a membranous structure called an envelope. Most viruses enter a host by binding to a host surface receptor and replication of viruses may be carried out by host or viral enzymes depending on the virus. All viruses lack protein synthesis machinery & depend on host cell for viral protein translation & virus assembly.  Immunity to viruses: Disease mechanisms Progeny virions from an infected host cell attack nearby host cells & lead to widespread dissemination of virus. Progeny virions that reach blood can spread systemically. Viruses cause disease both directly or indirectly. Viruses usually kill or at least inactivate host cell’ functions such that clinical symptoms appear. Immune response to viral infection mostly damages host tissues & induce inflammation & causes immunopathic disease. Clinician classify viral diseases as either acute or chronic.  Immunity to viruses: Disease mechanisms When a host is initially infected with the virus, host experience the acute disease which may be mild or severe (depends on virus virulence) but is of short-term duration. Sometimes viruses are not completely eliminated and establish persistent infections and may cause long-term or recurrent illnesses that are considered chronic diseases. In some cases, virus become latent without causing any disease but cause severe disease when reactivated. Example: – Reactivation of Varicella zoster virus (VZV) which causes ‘chicken pox’ in young children, precipitates a painful condition called ‘shingles’ in adults.  Immune effector mechanisms to viruses Clathrin-mediated endocytosis or phagocytosis of virions or activation by viral PAMPs. Fig 13.3: Major mechanisms of Read details from immune defense against viruses. the text book.  Immune effector mechanisms to viruses Fig 13.3: Major mechanisms of Read details from immune defense against viruses. the text book. Evasion strategies of viruses  Antigenic variation A common way for a virus to hide from the host immune system is to change its antigenic epitopes over successive generations. The rapid and mostly minor modification of viral antigens through random mutations is known as ‘antigenic drift’. For example, influenza virus can not proofread its RNA genome during replication & sustains a high rate of mutation & show ‘antigenic drift’ from one generation to another. Antigenic shift: Fig. 13.4: Principle of antigenic shift Evasion strategies of viruses Evasion strategies of viruses Immunity to parasites: Disease mechanisms Parasites include unicellular protozoa & multicellular worms and they claims millions of lives every year, particularly in developing countries. Some protozoans replicate extracellularly, whereas others replicate intracellularly. Helminth worms reproduce inside a host’s body but outside its cells or entirely outside the host. Immunity to parasites: Disease mechanisms Many parasites have multistage life cycles, and each stage of a parasite may be able to infect a different host species. Parasites also frequently use vectors to infect their ultimate hosts, or serve as vectors for other types of pathogens. For example, human contract malaria through the bite of an Anopheles mosquito infected with the protozoan parasite Plasmodium falciparum.  Immune effector mechanisms to parasites Different parasites evoke different types of immune responses, depending on the size and cellularity of the invader and its life cycle. In general, protozoan parasites tend to induce Th1 responses, while helminth worm infections and attacks by ectoparasites are usually handled by Th2 responses.  Defense against protozoans 1. Induced innate defense: a) Many protozoan components act as PAMPs for TLRs. b) Certain stages of Plasmodium species produce PAMPs that activate plasmacytoid DCs (pDCs) to produce IFNs. c) Complement activation via MBL-induced lectin pathway is also important for fighting Plasmodium falciparum & other Plasmodium species that cause malaria. d) Many single nucleotide polymorphisms (SNPs) in TLRs, complement receptor & acute phase protein CRP (C- reactive protein) effect resistance or susceptibility to malaria.  Defense against protozoans 2. Humoral defense: a) All the effector mechanisms ascribed to antibodies for defense against extracellular bacteria (refer to Fig 13.1) apply to defense against small extracellular protozoans. b) Anti-parasite Abs mediate neutralization, opsonized phagocytosis, and/or classical complement activation. c) Larger extracellular protozoans can be dispatched by ADCC mediated by neutrophils and macrophages.  Defense against protozoans 3. Th1 responses, IFN-g and macrophage hyperactivation a) Th1 response is critical for anti-protozoan defense because Th1 effectors are key sources of IFN-g needed for macrophage hyperactivation. b) Like many intracellular bacteria, many protozoan parasites (e.g. Leishmania major) infect or taken up by macrophages but are not destroyed within ordinary phagosomes. c) Only in hyperactivated macrophages are sufficient levels of ROIs and RNIs produced to efficiently kill such parasites. d) TNF secreted by hyperactivated macrophages plays an important role in control of protozoans. e) If hyperactive macrophages can not clear the parasite, a ‘granuloma’ is formed that encompasses the infected host cells and walls off the invader.  Defense against protozoans 3. Th1 responses, IFN-g & macrophage hyperactivation-Cont’d IFN-g has many other anti-protozoan effects as this a) Is directly cytotoxic to various form of many parasites. b) Stimulates IL-12 production by DCs & macrophages, which triggers additional IFN-g production by NK & NKT cells. c) Induces iNOS expression in infected macrophages, resulting in NO production that kills the parasite or infected cell. d) Upregulates the expression of enzymes necessary for phagosome maturation. e) Upregulates Fas on infected macrophages so that they can be killed by FasL-expressing T cells.  Defense against protozoans As Th2 cytokines (TGF-b, IL-4, IL-10 & IL-13) inhibit IFN-g production & suppress iNOS, individuals that mount Th2 responses instead of Th1 responses are highly susceptible to diseases caused by protozoan parasites.  Defense against protozoans 4. CTLs and gd T cells – If a protozoan parasite escapes from a macrophage phagosome into cytosol, then parasite Ag may be presented by MHC class I. – The infected host cells then becomes target for CTLs. – However, perforin/granzyme-mediated cytolysis is not very effective against acute protozoan infections but IFN-g secreted by CTLs plays important role in anti-protozoan responses. – Similarly, IFN-g secreted by activated gd T cells can bolster the body’s defenses during the early stages of protozoan infections. – Perforin/granzymes-mediated cytotoxicity becomes important for controlling chronic stages of protozoan infections.  Defense against helminth worms Induced innate defense: – Not much mechanistic details are known. – However, in mice, TLR4 is important for fighting the blood- dwelling trematode Schistosoma mansonii. Th2 responses and humoral defense: – While Th1 responses are needed to combat protozoan parasites, Th2 responses are vital for eliminating helminth worms. – Check Fig 13.5 on next slide.  Defense against helminth worms Read details from the textbook Fig 13.5: Major mechanisms of immune defense against helminth worm parasites. Evasion of the immune system by parasites A parasite that has a multistage life cycle enjoys a wealth of opportunities to thwart the immune response. Several evasion strategies used by protozoa and/or helminth worms include 1. Avoiding antibodies 2. Avoiding phagolysosomal destruction. 3. Avoiding complement. 4. Interfering or modulating host T cell responses  Immunity to Fungi: Disease mechanisms Fungi are either unicellular and grow as discrete eukaryotic cell (like yeast) or are multicellular and grow in a mass (mycelium) of filamentous processes (hyphae). Dimorphic fungi adopt a unicellular form at one stage in their life cycle and a multicellular form in another stage. Fungi called dermatophytes infect the skin, hair and nails.  Immunity to Fungi: Disease mechanisms Most fungal species are not harmful to healthy humans, but they can cause significant harm when become invasive. Fungi are a significant clinical threat for individuals undergoing organ transplant, treatment for autoimmunity, & chemotherapy as they induce immunosuppression. In particular, species of Aspergillus, Candida and Cryptococcus fungi have become prominent threats to immunocompromised individuals. Immune effector mechanisms against fungi Read details from text book. Fig 13.6.  Evasion of the immune system by fungi Many fungi adopt different morphological forms at different stages in their life cycle, affording them multiple opportunities to evade immune defense. Fungi use many different strategies to 1. Avoid detection by PRRs. 2. Avoid phagocytes. 3. Avoid complement. 4. Promote a less effective Th response 5. Avoid antibodies  Prions Prions are the pathogens that cause spongiform encephalopathies (SEs), which are rare, lethal neurodegenerative diseases characterized by lesions that render the brain ‘sponge-like’. The major humans SEs are variant Creutzfeldt-Jakob disease (vCJD) and Kuru. Animal SEs include ‘scrapie’ in sheep & bovine spongiform encephalopathy (BSE, or mad cow disease) in cattle. These disorders are associated with the ingestion of infected tissues from an animal suffering from an SE. Prions are essentially transmissible proteins devoid of nucleic acid.  Prions Normal prion protein is denoted as PrPc (prion protein, cellular) and the altered protein is denoted as PrPres. When PrPres is introduced into a healthy animals, it acts as a template for the refolding of existing host PrPc molecules into additional copies of PrPres. The misfolded PrPres protein has profoundly altered properties compared to PrPc and causes clinical signs of SE. Prion infection destroys the brain without inducing either a humoral or cell-mediated adaptive response. Host’s T cells are usually tolerant to the infectious PrPres protein. Recent evidence indicate that innate defense against prion does exist & may help to slow the course of SE disease.  Next Lecture Chapter 18: Immune Hypersensitivity.