Immunology - Microbial Infection (Extra) Flashcards
viruses (general)
obligate intracellular parasite, each viral particle or virion consists of a single nucleic acid (RNA or DNA) encoding the viral genome surrounded by a protein coat, capable of replication only within the living cells of bacteria/animals/plants, classified into different orders and families by consideration of the type of nucleic acid present (RNA or DNA) + whether the nucleic acid is single- or double-stranded, + presence or absence of an envelope
viruses (structure)
protective protein coat (capsid, shape varies from simple helical and icosahedra forms to more complex structures with tails, provides protection for the viral genome against the environment, functions in receptor recognition + targeting the virus to a susceptible host and cell type), some have a phospholipid envelope (derived from the infected host’s cell membrane that surrounds the protein capsid), inserted into the lipid envelope there are usually viral encoded proteins known as spike projections (typically glycoproteins and are also involved in receptor recognition and viral tropism, ie neuraminidase and haemagglutinin glycoproteins expressed on the surface of the influenza A virus)
Viruses (tropism - general)
most abundant and diverse pathogens on earth, millions of years of evolution in close proximity to their hosts has resulted in highly precise mechanisms in which they target and infect host cells, first stage of viral tropism is determined by the route of infection needed to gain access to the specific host tissue (ie influenza A virus is transmitted through infected aerosols during coughing and sneezing which allows the virus direct access to the respiratory tract where its target cells are located), after gaining access to the specific host tissue target cell infection is achieved at the initial stage of virus replication when the virus recognises and binds to a receptor on the target cell surface
Viruses (tropism - examples)
virus/target/receptor
- EBV/B cells /compliment receptor 2
- HIV/T cells and monocytes/CD4, CXCR4 or CCR5
- Influenza/respiratory epithelium/sialic acid residues
- Rhinovirus/nasal epithelium/ICAM-1
Virus replication
cannot occur without the machinery and metabolism of a host cell, although the replicative life cycle differs greatly between species and category of virus there are six basic stages that are essential for viral replication
- Attachment: Viral proteins on the capsid or phospholipid envelope interact with specific receptors on the host cellular surface, this specificity determines the host range (tropism) of a virus
- Penetration: The process of attachment to a specific receptor can induce conformational changes in viral capsid proteins or the lipid envelope that results in the fusion of viral and cellular membranes, some DNA viruses can also enter the host cell through receptor-mediated endocytosis
- Uncoating: The viral capsid is removed and degraded by viral enzymes or host enzymes releasing the viral genomic nucleic acid
- Replication: After the viral genome has been uncoated transcription or translation of the viral genome is initiated, this stage of viral replication differs greatly between DNA and RNA viruses and viruses with opposite nucleic acid polarity, culminates in the de novo synthesis of viral proteins and genome
- Assembly: After de novo synthesis of viral genome and proteins which can be post-transcriptionally modified viral proteins are packaged with newly replicated viral genome into new virions that are ready for release from the host cell, aka maturation
- Virion release: There are two methods of viral release (lysis or budding), lysis results in the death of an infected host cell (these types of viruses are referred to as cytolytic, ie variola major aka smallpox), enveloped viruses such as influenza A virus are typically released from the host cell by budding (this process that results in the acquisition of the viral phospholipid envelope, these types of virus do not usually kill the infected cell and are termed cytopathic viruses)
After virion release some viral proteins remain within the host’s cell membrane, which acts as potential targets for circulating antibodies, residual viral proteins that remain within the cytoplasm of the host cell can be processed and presented at the cell surface on MHC class-I molecules where they are recognised by T cells
TB general
caused by infection with Mycobacterium tuberculosis (non-motile, slow-growing, rod-shaped bacillus), spread via respiratory droplets that contain the tubercle bacillus, while most droplets will be stopped from entering the body by the physical barriers found in the upper respiratory tract those less than 1-2 µm reach the lower respiratory tract and lungs, the outcome of infection is dependent on the protective power of the host’s immune system and the pathogenicity of the bacteria, majority of individuals will be able to control infection and contain it within a granuloma (aggregate of immune cells that walls off the mycobacteria but does not eradicate them), as bacteria are still present, the infection is described as latent and the individual is at risk of future reactivation of disease if they become immunocompromised
TB immune response
first cells encountered by the mycobacteria in the lung = alveolar macrophages (phagocytes which respond to invading pathogens in a non-specific manner and provide an initial line of defence), macrophages and other antigen presenting cells (APCs) recognise and phagocytose the mycobacteria engulfing them into a phagosome which matures and fuses with endosomes and lysosomes, the environment becomes acidic and nutrient-poor and the bacteria are exposed to antimicrobial peptides and degrading lysosomal enzymes ie lysozyme, pathogenic mycobacteria have developed mechanisms to subvert the host defences by blocking phagosomal maturation in resting macrophages however activation of macrophages by the cytokine interferon-γ (IFNγ) promotes bacterial killing via the formation of toxic reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI), activated macrophages also release an array of cytokines and chemokines including tumour necrosis factor α (TNFα) which induce a pro-inflammatory response and direct immune cells to the site of infection, APCs known as dendritic cells together with activated macrophages are able to process antigen and present components on their surface in conjunction with MHC class II molecules, dendritic cells migrate to draining lymph nodes where they encounter large numbers of naive T cells, naive CD4+ T cells sample antigen/MHC complexes on the surface of migrating APCs, after recognising the antigen/MHC complex specific for its T-cell receptor (TCR) the CD4+ cells become activated, proliferate and in the presence of proinflammatory cytokines such as IFNγ and IL12 differentiate into T helper (Th)-1 cells, Th1 effector cells migrate back to the lungs via chemokine gradients produced by inflammation at the site of infection where they interact with MHC/antigen complexes on the surface of infected macrophages and produce a range of cytokines including IFNγ leading to further activation of macrophages and triggering the potent antimicrobial activities of the primed Th1 cells, a combination of innate and Th1-dominant adaptive immune responses culminates in the development of granulomas (the infiltration of cells into the lungs during the early innate response becomes organised into a primary granuloma with centrally located macrophages which leads to the formation of a larger well-organised solid granuloma when adaptive immunity is initiated with the infiltration of specific T lymphocytes and also CD8+, NK and γδT cells, macrophages at the centre will often be infected, have an activated appearance or be differentiated into epitheloid cells (some also combine to form giant multinucleated cells), the centre of the granuloma may exhibit caseous necrosis and have a cheese-like appearance, if the infection continues the centre may liquefy producing an environment in which the bacteria can grow extracellularly, cavitation may occur if the liquefied contents are released into the bronchial tree where they can then be expelled externally and the infection transmitted to others, more commonly the granulomas will undergo fibrosis or calcification and the infection is contained and becomes latent)
Malaria - key facts
particularly affecting children under 5 and pregnant women, more than 90% of the disease burden is in sub-Saharan Africa where climate conditions are favourable for the mosquito vector to thrive but malaria continues to cause considerable morbidity in Asia and south America
Malaria - life cycle
intracellular parasite transmitted through the bite of a female Anopheles mosquito, of the five Plasmodium species that are known to infect humans P.falciparum causes the majority of infections (and deaths), during a mosquito bite sporozoites are released from the mosquito salivary glands into the host’s skin + enter the bloodstream and circulate to the liver and invade hepatocytes and differentiate (pre-erythrocytic stage, infection not apparent clinically), after approximately one week each infected liver cell will rupture, releasing as many as 30,000 merozoites into the bloodstream where they invade red blood cells (RBCs), each parasite develops maturing from rings to trophozoites to fully formed mature schizonts (each of which contains 16-20 merozoites) over a period of 44-72 hrs (depending on species), the schizonts rupture to release more merozoites into the bloodstream where they invade new RBCs, starting a new cycle (erythrocytic or blood-stage, during the rupturing of the RBCs and the release of merozoites into the bloodstream acute clinical symptoms of malaria (fever, headache, nausea) are manifested), severe malaria is caused by excessive RBC rupture (leading to anaemia) + excessive inflammation and accumulation of infected RBCs (iRBCs) in small blood vessels (leading to organ damage), a small proportion of merozoites develop into male and female gametocytes and are taken up by biting mosquitoes, within the mosquito gut fertilisation occurs + the zygote undergoes meiosis and thousands of sporozoites are produced completing the cycle
Malaria - Immune response to the pre-erythrocytic stage
naturally acquired not very effective as evidenced by recurrent infections throughout life in residents of endemic areas, antibodies (Abs) are eventually developed against the most abundant surface protein on the sporozoite (the circumsporozoite protein) which trap sporozoites in the skin and reduce their invasion into liver cells by inhibiting their motility, infected liver cells can be destroyed by Ab-dependent cellular cytotoxicity or by the action of interferon-gamma producing CD4+ and CD8+ T cells, NK cells and gammadelta T cells which induce final effectors such as nitric oxide
Malaria - Immune response to the blood stages
pro-inflammatory cytokine response involving IL-1beta + IL-6 + IFNgamma + TNFalpha and IL-12, enhances phagocytosis and killing of iRBCs by macrophages, over-production of these cytokines contributes to malarial pathology and down regulation of inflammation (by IL-10 and TGF-beta) once parasitaemia is under control is required to prevent severe disease, phagocytosis of iRBC is augmented by their opsonisation by cytophilic Abs binding to parasite antigens exported to the RBC surface, these antigens are highly polymorphic and undergo clonal antigenic variation meaning that effective opsonisation (or prevention of iRBC sequestration in blood vessels) may only develop after many and varied malaria infections, antigens expressed on merozoites are also polymorphic but Abs against conserved or semi-conserved epitopes can inhibit merozoite invasion of RBCs, complement- fixing Abs against gametocyte and gamete antigens can prevent the establishment of infection in the mosquito and thereby block malaria transmission
Candida albicans - general
infections broadly divided into two groups (mucosal and systemic), mucosal infections present commonly in otherwise healthy women as vulvovaginal candidiasis (thrush) which up to 75% adult women will experience at least once in their lifetime, C. albicans can also colonise the mouth (oral candidiasis) and can be a problem in newborns and the elderly, systemic infection or disseminated candidiasis is a much more serious disease, occurs when a patient is immunosuppressed (due to immunosuppressive drugs, chemotherapy or neutropenia) and C. albicans, normally kept under control by the immune system invades tissues and enters the bloodstream, C. albicans commonly lives in the human gut therefore invasion of the gut wall by C. albicans (ie through an ulcer or wound) is thought to be one way in which disseminated candidiasis can start, C. albicans is able to grow on medical devices such as intravenous catheters and this is another way in which patients may become exposed to C. albicans while in the hospital
C. albicans - morphological forms
a budding yeast +
pseudohyphae +
filamentous hyphae, ability to switch between these forms is controlled by a highly complex genetic network and is dependent on a number of environmental factors, hyphae are thought to be more virulent since expression of toxins are associated with this morphology, Candidalysin is a toxin secreted by hyphae that damages epithelial cells and thus may allow C. albicans to penetrate barrier tissues and establish infections, Yeast are small round cells that divide by conventional cell division, true hyphae are elongated cells that do not separate following cell division and are separated by specialised septa that allow passage of cytoplasm and other components between compartments, Pseudohyphae are less elongated hyphae which are more constricted at septa than true hyphae
C. albicans - immunity
pattern recognition receptor,
Dectin-1 and its signaling molecule CARD9 (Dectin-1/CARD9 is expressed by innate myeloid cells such as monocytes + dendritic cells + neutrophils, Dectin-1 is required for the efficient phagocytosis and killing of C. albicans because it binds β-glucans which form a layer within the C. albicans cell wall, CARD9 is needed for Dectin-1 responses since it transmits the signals to the rest of the cell and is required for production of pro-inflammatory cytokines and activation of important transcription factors), deficiency in CARD9 predisposes to disseminated candidiasis but only affects the brain and central nervous system (because CARD9 is important for recruiting neutrophils to the brain after infection by activating the production of chemokines from neutrophils themselves and resident myeloid cells in the brain)
HIV - general
member of the retrovirus family, causative agent of acquired immunodeficiency syndrome (AIDS), invades various immune cells (ie CD4+ T cells and monocytes) resulting in a decline in CD4+ T cell numbers below the critical level and loss of cell-mediated immunity, the body becomes progressively more susceptible to opportunistic infections and cancer
