Quiz 8

lecture 16 and 17

what is a failure to detect non-self

infection

What are the routes of infection by a pathogen

aerosol: inhalation, oral: ingestion, food or water, vector-borne, fomites, zoonotic, bloodborne

aersols

within and beyond 1 meter, can float in the air for hours, can be inhaled,

droplets

can travel less than 1 meter, fall to the ground in under 5 seconds, cannot be inhaled

aerosols vs. droplets

Size determines distance and duration in the air. Determines whether social distancing works

foodborne illnesses

Salmonella, E. coli, Listeria monocytogenes

waterborne illnesses

E. coli, Shigella, Legionella, Vibrio cholerae, Helicobacter pylori

vectorborne

bites by fleas, ticks, mosquitoes, biting flies

ectoparasites

fleas can carry infectious disease, cat scratch disease (Bartonella henselae) in flea feces, Y. pestis to humans

borrelia burgdoferi

causative agent of Lyme disease, transmitted by ticks, produces a classic bull’s-eye rash within several days of infection

fomites

Inanimate objects that can become contaminated with pathogens, for example, objects that contaminated droplets fall onto. Hospital-acquired MRSA infection

zoonotic

Disease spreads from animals to humans. Can be spread by any of the routes (oral, direct contact, fomites, etc)

examples of bacterial zoonotic diseases

anthrax, brucellosis, bovine tuberculosis, listeriosis, salmonellosis, and leptospirosis

transmission routes of bloodborne illnesses

shared needles, mucous membrane exposure: mouth, eye, nose, sexual contact, blood transfusions

bacteria

Prokaryotes, single-celled organisms, can be free-living, and lack a distinct membrane-bound nucleus

Which components of the immune system are important for bacterial infections

neutrophils, macrophage, dendritic cell, B cell, TH17, TH1, and CD8

innate immune mechanisms to control bacterial infections

opsonization, membrane attack complex formation by activation of the complement cascade, antimicrobial peptides: defensins, and commensal microbiota

cell-mediated innate immune anti-bacterial mechanisms: macrophages and neutrophils

innate sensing by PRRs, phagocytosis, respiratory burst, and neutrophils (NETs)

CD8+ T cell cytolytic function: the kiss of death

Upon antigen recognition of a target cell, CD8+ T cells become polarized, redistributing the contents of the cytoplasm to align lytic granules closest to the target cell. Lytic granules contain perforin and granzyme B, which are released at the target cell synapse

Th1 CD4+ T cells are protective against intracellular bacterial infections

Th1 cells activate infected macrophages through IFNγ production and CD40L signaling. Activated macrophages can fight intracellular infections by increasing phagolysosomal fusion, reactive oxygen species (ROS), and reactive nitrogen intermediates (RNI), which destroy the intracellular pathogen

What are the protective functions of IL-17 produced by Th17 CD4+ T cells that protect against extracellular bacterial infections

macrophage and neutrophil activation, enhanced phagocytosis, production of antimicrobial peptides, and enhanced barrier function of epithelial cells

CD4+ T follicular helper cells (Tfh)

Tfh migrate to the B cell area of lymph nodes, Tfh provide help signals to B cells, master TF: Bcl-6

antibodies during bacterial infections

Because many bacteria use multiple mechanisms for cell entry, antibodies are less useful for blocking bacterial cell entry. During bacterial infections, antibodies are good for activating complement, opsonization, and neutralizing toxins

What is ineffective against bacteria

Neutralization does not work well for bacteria

Antigen evolution and variability of Streptococcus pneumoniae

immune evasion through surface antigen evolution, each strain displays a different capsular polysaccharide (serovar), antibodies produced by one infection are ineffective for infection with a different serovar

phagosomal escape to cytosol of Listeria monocytogenes

L. monocytogenes polymerize actin tails that help them rocket into the plasma membrane and generate long protrusions into unlabeled neighboring cells

legionella pneumophila block phagosome-lysosome fusion

LCV with features of ER, Golgi, and mitochondria, block of phagosomal acidification, block of phago-lysosomal fusion, altered vesicular trafficking, modulation of ubiquitination

mycobacterium tuberculosis block phagosome-lysosome fusion

inhibition of proinflammatory cytokine production, block of phagosomal acidification, block of fusion with LE and lysosomes, inhibition of autophagy and phagoccyte apoptosis, modification of phagocyte metabolism

superantigens

A class of antigens produced during bacterial or viral infections that leads to an excessive immune response. They bind to MHC II and then cross-link the TCR and CD28, leading to full T cell activation. The mucosal response to CD4+ T cell activation: vomiting and diarrhea

staphlococcus aureus

produces superantigens that lead to an excessive immune response: S. aureus enterotoxin B (SEB) and toxin shock syndrome toxin-1 (TSST-1)

mycobacterium tuberculosis

rod-shaped, acid-fast bacteria, discovered in 1882 by Robert Koch, the causative agent of Tuberculosis (TB)

How is tuberculosis transmitted and what does it infect

transmitted by aerosol and infects a cell type in the lung called a macrophage

What are the previous names of tuberculosis

phthisis, consumption, the white death, the great white plague

tuberculosis today

10.4 million people/year become sick with TB, 1.3 million people/year die of the disease, over 95% of TB deaths occur in low- and middle-income countries.

What 6 countries account for 60% of TB deaths

India, Indonesia, China, Nigeria, Pakistan, South Africa

How many hosts are there of mycobacteria

many hosts across the animal kingdom

granuloma

sites of containment and growth for mycobacteria, the immune system’s attempt to wall off the bacteria, infected macrophage core, lymphocytic cuff, macrophages fuse into multinucleated giant cells, often a necrotic or caseous core

types of granulomas

The immune response within the granuloma can determine the infection outcome

what is a virus

An infectious agent that lacks the ability to replicate outside of a host cell. A virus consists of nucleic acid in a protein coat. It can come in many different shapes and sizes

steps in a viral infection

1. Viral adherence to host cell

2. cell entry

3. Uncoating: shedding the envelope and capsid

4. Replication of genetic material: forcing the host cell to make viral proteins and glycoproteins

5. assembly of new viral particles

6. viral egress: through lysis or budding

viral adherence is an important step in the lifecycle

Viruses use their surface molecules (glycoproteins) to attach to specific receptors on host cells. The nature, number, and cell distribution of the receptor determine the tissue tropism of the virus

What is the receptor of rabies virus

acetylcholine receptor (found on post-synaptic membranes in the brain)

What is the receptor of HIV

CD4 and CCR5 or CXCR4 on T cells and macrophages

What is the receptor of SARS-CoV2

ACE2- angiotensin-converting enzyme on lung and gut epithelial cells

mechanisms of antiviral immunity, multi-step process involves:

1. production of pro-inflammatory cytokines, especially type I interferons

2. NK cell-mediated killing

3. T cell-mediated killing and activation

4. antibodies

type I IFN

produced by innate cells (monocytes, macrophages, dendritic cells) and by epithelial cells, especially infected cells, activates and induces proliferation in NK cells, activates macrophages and dendritic cells to produce interferon-stimulated genes (ISGs) with antiviral properties

NK cell mechanism of antiviral immunity

NK cells kill infected cells through the release of lytic granules

What cell types have important roles during viral infections

CD8+ T cells, TH1 cell, Tfh cells

Th1 CD4+ T cells are protective against intracellular bacterial and viral infections

Th1 cells activate infected macrophages through IFHgamma production and CD40L signaling, and activated macrophages are better at fighting intracellular viral infections

mechanisms of antiviral immunity CD8+ T cells

CD8+ T cells kill infected cells through lytic granules containing perforin and granzyme B and the kiss of death

linked recognition

B cells require T cell help from Tfh cells for antibody production. Tfh cells recognize a peptide derived from the antigen bound by the B-cell receptor

mechanisms of antiviral immunity: antibodies

Dimeric IgA: very good at neutralization (blocking viral entry), especially at mucosal surfaces. IgG, IgM, and IgA: all circulating antibodies have the capacity to block viral entry. IgG: enhances phagocytosis of viral particles through Fc gamma receptors (opsonization)

Influenza is categorized by the presence of two proteins:

Hemagglutinin is used to adhere to host cells, and neuraminidase is an enzyme used to enter host cells

Antigen drift

Error-prone RNA polymerase leads to the accumulation of small mutations over each replication cycle. These mutations can alter immune epitopes. These strains will cause disease because individuals will not carry antibodies to these new epitopes> mild outbreaks

Antigen shift

Influenza genomes are made up of 8 ssRNA segments; the segmented genome allows for genomic mixing following co-infection of two different strains within 1 host. Genetic reassortment leads to new strains carrying entirely new proteins that no one has immunity against, which can cause a big epidemic or a pandemic

viral latency

a form of dormancy or non-replication

herpesvirus latency

Following primary infection, the herpesvirus stops being lytic and becomes dormant in the presence of immune pressure. The virus only reactivates if the host becomes immunocompromised (stress, aging, immunosuppressive drugs)

Herpes-simplex virus (HSV-1)

initial infection around the mouth is cleared by the immune response (cold sores). The virus enters neurons to exist in a latent state; upon reactivation, the virus reinfects epithelial cells, causing a new round of cold sores

cytomegalovirus (CMV)

One way herpesvirus achieves latency is by downregulating MHC class I (minimizes the ability of CD8+ T cells to control the virus)

What cells should be triggered by a reduction in MHC class I

NK cells

NK cells’ inhibitory signals monitor MHC I expression

CD94:NKG2A recognizes HLA-E on the target cell and stops NK cell killing. HLA-E binds the leader sequence of HLA-A, -B, or -C, and so the surface expression of HLA-E is directly correlated with HLA expression

CD94: NKG2A recognizes HLA-E on target cell

A damaged or infected cell with low HLA-E expression will not mount an inhibitory signal. If the NK cell engages activating signals without inhibitory ones, it will kill its target. It’s all about the balance between activating and inhibitory signaling

immune evasion by herpesvirus

So CMV also targets NK cell recognition. CMV protein upregulates HLA-E and inhibits NK cell degranulation

Varicella-zoster virus: the causative agent of chickenpox

Primary infection in mucosal epithelial cells in the upper respiratory tract. Latent infection is established in the dorsal root ganglia. Reactivation is known as shingles, which commonly appears with aging

Feline coronavirus (FCoV)

An alpha-coronavirus (SARS-CoV-2 is a beta-coronavirus) causes feline infectious peritonitis (FIP), spread via fecal-oral transmission. It is usually asymptomatic, making diagnosis challenging. Virulent strains can replicate in macrophages and monocytes, leading to immune system activation and inflammation. FCoV prevents the expression of viral antigens on the surface of infected cells, blocking antibody-dependent phagocytosis and cytotoxicity

SARS-CoV-2 steps in viral infection

1. Viral adherence to the host cell

2. cell entry

3. uncoating: release of the viral genome into the cytoplasm

4. Replication of genetic material: forcing the host cell to make viral genomes and viral proteins

5. Assembly of new viral particles

6. Viral budding and release of new SARS-CoV-2 virions

How is SARS-CoV-2 spread

By aerosol, droplet formation, and droplet contamination of surfaces (fomites). social distancing only works if droplets are the dominant form of transmission

mild Co-Vs versus severe disease is determined:

By the speed and efficacy of the 3 different immune arms: innate immunity, T cells, and antibodies

severe COVID-19

associated with a delayed early response and a paradoxical hyper-inflammatory late response

long COVID chronic condition

more than 50 long-term effects of COVID-19: a systemic review and meta-analysis

What explains post-acute sequelae of SARS-CoV-2 (PASC) or long covid

1. pathogen reservoir

2. autoimmunity

3. microbiome dysbiosis

4. tissue damage

Viral infections with documented PASC:

ebola, dengue, chikungunya, EBV, polio, West nile, VZV

SARS-CoV-2 infections in wild animal populations

Researchers found 23.5% of deer in Ohio had been infected. Evidence of human-to-deer spillover is based on circulating human vs. deer variants. Evidence of deer-to-deer transmission based on variant clusters

SARS-CoV-2 evasion of immunity: variants of concern

XFG= stratus and NB. 1.8.1 nimbus

stratus

is the result of a recombination event between two other Omicron strains

How do viral mutations evade immunity step 1

mutations alter the epitopes recognized by antibodies and prevent antibody binding and neutralization

How do viral mutations evade immunity step 2

Mutations could also change the peptides recognized by T cells. For SARS-CoV-2, T cell responses are sustained DESPITE new variants

antibodies provide:

protection from infection (POI) without specific antibodies, a person is likely to get infected if exposed

T cells provide:

protection from disease (POD) without specific T cells, a person is likely to end up with severe disease, become hospitalized, and potentially die

How do COVID-19 vaccines elicit protection

Vaccines generate spike-specific effector T cells, memory T cells, memory B cells, and plasma cells. Vaccines generate spike proteins and stimulate innate responses