Lecture 8 - Host Responses to Viral and Bacterial Infections

viruses

genetic material wrapped in protein, could be DNA or RNA based, nucleic acid may be single stranded or double stranded, obligate intracellular parasites require a host for reproduction

DNA viruses

most stable

ssRNA viruses

least stable

viral modes of transmission

could be person to person through inhalation or direct contact with the respiratory tract, fecal so orally through ingestion, sexual contact or inoculation through the skin, vertical transmission (from mother to child transplacental or post-natal), blood and blood products or an arthropod vector

extracellular virion particles

a virion is what comes in to infect you, antibodies are good at targeting them, this type is more resistant to physical stress but susceptible to humoral control

intracellular genomes

they are susceptible to cell mediated immunity and persist in host cells by limiting their gene expression (stay hidden/latent infection), this means there is always a reservoir the virus can come back from, evolved mechanisms to evade the host immune repsonse,

why are viruses considered an immunological challenge?

because they can hijack host cell machinery to replicate so its hard to target without damaging the host, they replicate inside cells so many extracellular immune mechanisms can’t reach them once infection is established so the antibody response is useless for a cell thats infect with a virus, they mutate rapidly because they have error prone polymerases, there is no proofreading machinery so the mutation rate is high and there is antigenic variation (basically means any immune response is useless cause the virus is constantly evolving, they can also infect immune cells, disarming the immune system

HIV

virus that infects CD4 T cells and macrophages, disarming the immune system, it uses Vif protein to target APOBEC3G which degrades restriction factor and allows replication

EBV

infects B cells

how do you destroy a virus that is hiding inside your own cells without harming yourself?

this is why MHC I and CTLs exist, NK cells evolved and IFNs are needed

viral elements in our genome

8% of our genome is made of endogenous retroviral sequences (ERVs) and 45% is derived from transposable elements of viral origin (includes LINEs, SINEs and DNA transposons which comes from viral interactions, the placenta relies of retroviral elements to form

what are the immune events in a viral infection?

the virus is detect by PRRs, type 1 IFN production starts leading to antiviral state in neighboring cells, the NK cells are activated, killing infected cells and producing IFNy leading to macrophage activation, the peak of IFNy production causes ISG expression leading to viral replication slowing, DCs mature starting to present antigen to T cells, after a few days first antigen-specific T cells appear, after a week effector CTLs appear in the blood trafficking to the infection site, this peaks and the virus starts to clear while B cells are activated in germinal centers, the first IgG antibodies appear leading to neutralization and viral load starts to decline, the germinal center reaction is ongoing leading to affinity maturation and high affinity antibodies, then after 4 weeks the infection is cleared leading to a contraction phase where memory cells are established and then you get long lived plasma cells in the bone marrow that patrol your immune system incase the virus appears again

innate response

while the adaptive response is developing you only have the innate one available to control the virus and the levels rise, in early stages the viral load continues to increase until adaptive immune response jumps in then it goes down

viral PAMPs

pathogen associated molecular patterns, they are nucleic acids that look different from host nucleic acids or are in the wrong place which is why they trigger a response, includes 5-triphosphate RNA, dsRNA, cytosolic dsDNA, unmethylated CpG DNA and uncapped ssRNA

5’ triphosphate RNA

generated during viral replication, not normally found in host cytosol

double-stranded RNA (dsRNA)

produced by virtually all replicating viruses, doesn’t exist in the host

cytosolic dsDNA

in the cytosol for viruses, only in nucleus for host

unmethylated CpG DNA

found in viral genomes but methylated in host genome

uncapped ssRNA

host mRNA is capped

pattern recognition receptors (PRRs)

includes RIG-I-like receptors (RLRs) which detect cytosolic dsRNA/ssRN, RIG-I are short dsRNA and 5’-triphosphate ssRNA (flaviviruses,orthomyxoviruses) + MDA5 which is a long dsRNA (picoronaviruses), cGAS-STING is a cytosolic DNA sensor (poxviruses), these are key in starting the antiviral immune response

toll-like receptors (TLRs)

they are within endosomes and detect viral RNA/DNA, TLR3 is a dsRNA (westnile), TLR7/8 is an ssRNA (influenza, HIV) and TLR9 is an unmethylated CpG DNA (herpesviruses), the ones found at the cell surface detect envelope glycoproteins (TLR4 - RSV and ebola, TLR2 - measles, vaccinia)

interferon response/antiviral alarm system

PRR activation will activate Type 1 interferon alpha + beta which are the most important step in antiviral response as it starts the antiviral response warning other cells they might get infected too by activating interferon stimulated genes and cells in the paracrine and endocrine systems play a role, it is very fast from minutes to hours post infection, causes increase resistance to infection and enhances anti-viral response, it interferes with viral replication by upregulating MHCI, activating NK cells, promoting DC maturation and induction apoptosis of infected cells

ISGs

shuts down viral replication, includes protein kinase R (PKR) which phosphorylates eIF2a shutting down protein synthesis which stops viral replication cause you need this to work so the virus can hack host synthesis mechanisms, OAS/RNase L degrades viral RNA’ Mx proteins block viral RNA synthesis especially influenza, IFIT proteins sequester viral RNA and tetherin (BST-2) tethers budding virions to the cell surface while APOBEC3G mutates viral DNA/RNA which inhibits viral replication

what happens when there is no IFN warning?

the cell gets infected but without warning the virus replicates freely, this spreads to neighbouring cells causing an overwhelming infection before adaptive immune response can develop which is late by 5-14 days

what happens when you get IFN warning?

after the cell is infected type 1 IFN is produced so neighbouring cells are armed, this causes viral spread to be blocked and adaptive immunity has time to develop so the response kicks in within hours

influenza

uses NS1 protein which gets sequestered in dsRNA and prevents RÙIG-I activation which blocks PRR signaling leading to viral evasion, blocks IFN-B production

ebola

targets VP35 which binds dsRNA and shields it from MDA5/RIG-I which blocks PRR signalling and allows viral evasion, blocks IFN-B transcription

SARS-CoV 2

has two mechanisms of viral evasion, the first is through ORF6 protein which blocks nuclear transport of STAT1 blocking ISG productiion and IFN stimulated response, or it generates double-membrane vesicles around viral replication intermediates and hides from cytosolic sensors

MHC 1 viral surveillance system

viruses hide within cells making them hard to eliminate but need to hijack ribosomes for viral protein synthesis, MHC 1 turns every nucleated cell into its own surveillance system, the viral proteins enter the MHC 1 pathway so the proteosome has viral peptides and TAP loads them then MHC1 displays them to warn immune system to prep an immune system, CTLs detect infection then non-self cells are killed, latent viruses dont replicate so they become invisible to the immune system

viral evasion strategies for MHC 1

for HIV the Nef protein targets MHC1 causing surface downregulation causing CTL evasion, for CMV either the protein US2/US11 targets MHC1 so it gets retrotranslocated leading to proteosomal degradation or US6 targets TAP blocking peptide loading onto MHC 1 cause without TAP you dont get loading of viral antigens, for HSV the ICP47 protein targets TAP blocking peptide transport into the ER

NK cells

they act as a counter measure to MHC 1 loss, they evolved to mitigate immune evasion cause they recognize infected cells with downregulated MHC 1, this missing self recognition acts as a loss of inhibitory signal leading to killing via perforin/granzyme and releases IFNy to prime macrophages, these cells + CTLS work together to eliminate viral infected cells

viral mechanisms for evading NK cells

for HIV the E7 protein targets IL18 receptor on NK cells inhibiting IFN production or the Nef protein targets MICA, ULBP1, 2 which downregulates NKG2D ligands, herpesvirus uses K5 decreasing expression of ICAM-1 which inhibits NK cell cytotoxicity, CMV either uses gpUL40 peptide to target NKG2A inhibitory receptor to mimic self and inhibit NK cells, it can also use UL18 which targets inhibitory KIR receptors creating a decoy MHC I which inhibits NK killing or use UL16/UL142 which targets ULBP1 1, 2,3 and 6 which down regulates NKG2D ligands

acute infection

the viral antigen leads to T cell activation, then the virus is controlled and the antigen is gone resulting in T cell memory

chronic infection

viral antigen leads to T cell activation and if it responds to anti-PD-1 the antigen persists so TOX is expressed leading to epigenetic remodeling and effector genes reducing IL2, TNF, IFNy and granzyme B which leads to exhaustion genes increasing like PD-1, TIM-3, LAG-3 and TIGIT but if there is no response to anti-PD1 the immune system is fully exhausted so all effectors are off so DNA methylation locks and exhaustion phenotype is permanent

viral latency

this is the ultimate immune evasion strategy, in an active infection viral proteins are expressed so peptides on MHCI result in killing via CTLs but with latent infect there are no viral proteins so immune system cant detect anything and the virus survives, features include silence so there is no viral gene expression, sanctuary so they hid in long lived, immune privileged cells and persistence so the genome is maintained without replication

what are the most common types of latent viruses?

VZV (resides in the sensory ganglia, persists via episomes and reactivates with stress and aging leading to shingles), HSV-1 (resides in trigeminal/cranial ganglia, persists via episome and reactivates with stress and fever leading to cold sores), EBV (resides in memory B cells, persists via episome and reactivates with immunosuppression leading to lymphoma risk), HIV (resides in CD4 T cells persisting as an integrated provirus and reactives with immune activation leading to AIDS if untreated) and CMV (resides in myeloid progenitor cells and monocytes which sometimes get antigen presentatiion so not completely latent, its an episome that gets reactivated via immunosuppresion, inflammation and myeloid differentiation leading to CMV pneumonitis, colitis or retinitis)

episome

segment of genetic material that is often a specific plasmid or viral DNA that can replicate independently within a cell’s cytoplasm or integrate into the host cell’s main chromosome

neutralizing antibodies

prevent viral infection by binding to viral surface proteins and blocking the virus from entering the cell, the best ones bind conserved target sites cause they are hard to mutate, broadly neutralizing ones target against viruses with dif antigen presentation so they are often used in vaccines

antigenic drift

evasion strategy by accumulating point mutations leading to error prone polymerase, no proof reading and fast replication, this causes gradual immune escape and is a strategy used in influenza, HIV and SARS-CoV2 (this is why we need booster shots for vaccines against these viruses)

antigenic shift

exchange gene segments between viral strains in a secondary host sot here is no cross-protective immunity to virus expression the novel hemagglutinin, pandemic generation, seen in influenza

glycan shield

an antibody evasion strategy, in HIV 50% of gp120 which is used for initiating attachment + infection of a new cell is covered in host-derived glycans, it hides conserved sites that broadly neutralizing antibodies need to target but glycosylation diverges leading to high density glycans, non self motif which is a target for potent neutralizing broadly neutralizing antibodies

decoy epitopes

highly visible, highly immunogenic epitopes that generate strong antibody responses but not neutralizing, basically just wastes energy making antibodies do things that wont get rid of the virus

cytokine storm

this is when dysregulated IFN and cytokine response results in tissue damage, seen in severe flu, COVID-19 and ebola

CD8 T-cell mediated immunopathology

CTLs killing of infected cells leads to organ damage and liver damage with hepatitis B virus infection

original antigenic sin

the idea that the first viral strain we encounter will be favored, memory response to the first influenza strain encountered dominates subsequent responses, suboptimal responses to novel ones

chronic immune activation

this causes accelerated immune aging, HIV co-morbidities like neurocognitive decline and cardiovascular disease

what is the HIV viral particle made of?

gp120 and 41 attaches the virus to the host cell, it has a lipid membrane that is host-derived, host proteins, matrix + capsid protein, transactivator of transcription (Tat), viral RNA genome, nucleocapsid, protease, reverse transcriptase and integrase

HIV transmission

sex is the most common method making up 85-90% of cases but its an inefficient transmission route as it only transfers .1 - .3% of the time, could be vertical so from mother to child where without therapy the risk is 15-40% but with therapy its 1-2% but with antiretroviral therapy before pregnancy its 0%, could also be through blood transfusion, IV drug use, contaminated needles or occupational exposure

HIV replication

there is attachment of the viral particle, then it gets endocytosed leading to release of the viral genome, reverse transcription, integration into the host genome which can be latent, transcription, translation and assembly + release

Gag, Pol and Env genes

they each encode large polypeptides that are cleaved into shorter proteins that have a particular function, Gag encodes core structural proteins like matrix, capsid and nucleocapsid proteins, pol encodes viral enzymes like protease, reverse transcriptase and integrase while env encodes envelope structural proteins like gp120 (non transmembrane envelope protein binding CD4, CCR5 on the host cell) and gp 41 (transmembrane envelope protein that is required for fusion of viral envelope and host cell membrane

Vif, Vpr and Vpu genes

encode accessory proteins that stabilize viral DNA, facilitate transport into the nucleus and promote the release of new virions

tat and Rev genes

consists of two exons each, their proteins regulate viral transcription and translation

Nef genes

encodes a negative factor that negatively affects the host cell survival and positively affects virus production in multiple ways

how does HIV directly kill CD4 T cells?

large amounts of virus are produced and the budding process can disrupt the cell membrane killing the cell or HIV hijacks cell machinery disrupting normal cell activities causing the cell to undergo apoptosis

bystander cell death

HIV binding to the surface of uninfected cells coated with antibody causes cell death by antibody-dependent cellular cytotoxicity (ADCC) or uninfected cells consume HIV proteins or particles which display HIV-derived peptides on MHC I leading to CTL killing

destruction of immune precursor cells

HIV infection leads to decreased bone marrow cellularity and abnormal changes in cellular structure, it can directly infect bone marrow stromal cells altering function or latently infect CD34+ bone marrow progenitor cells

the immune response to HIV

its chronic so it starts out acute getting flu like symptoms then eventually CD4+ T cells decrease causing the virus to comeback indicating AIDS stage of the virus via chronic immune activation + CD4+ T cell loss

HIV immune evasion

its fast cause of the rapid replication as several billion new viruses are made each day, antigenic drift means HIV reverse transcriptase is very prone to mistakes introducing new mutations and antigenic shift means recombination between different HIV viruses can occur generating new strains of the virus

HIV latency

the virus can integrate into the host DNA and stay dormant for months to years, the latent reservoir of the virus is established early and antiretroviral drugs cant eliminate a latent virus cause nothing to target, cure strategies focus on figuring out a way to activate latent HIV reservoirs so virus can be susceptible to antiretroviral treatment

antiretroviral drug evolution

combination of 3-4 antiretroviral drugs that target different retroviral cycle steps can reduce virus to undetectable levels and restore CD4 count, long lasting injectables leading to major reduction in death rates, life expectancy extended and now a mother with HIV can have an HIV free kid, its expensive cause unaffordable in most places there is a high pill burden cause you need to take it everyday and significant side effects, non-compliance leads to drug resistance too so testing long term injectables + prep

treatment as prevention

chances of transmission via sexual intercourse is zero when someone has been on ART for a minimum of 6 months so viral load is undetectable so its untransmissible, can also use prep to prevent HIV infection

berlin HIV patient case

an american studying in berlin was diagnosed with HIV and started therapy then after he was diagnosed with acute myeloid leukemia (AML), he received HSCs from a donor with a CCR5delta32 mutation which is an HIV receptor but when mutated it prevents the binding of the receptor making the immune system HIV resistant, they stopped ART therapy and after a year his HIV levels declined and CD4 T cell count increased, staying HIV free until his death, up to 5 ppl were cured so far and early treatment in newborn is encouraged

HIV vaccines failures and successes

the merck vaccine was an adenovirus gag/pol/nef trivalent vaccine but study ended early cause of higher HIV infection in the vaccine arm, HIV vaccine trials network had a DNA prime/boost vaccine made of DNA plasmid gag/pol/nef/env and and rAd5 gag-pol/env but it stopped due to data showing it was ineffective at preventing infection and lowering viral load in those infected, in 2009 thailand there was a prime viral vector with env, gag, pol and a boost made of recombinant canarypox vector vaccine with recombinant gp120 subunit vaccine it was 31% efficient but it did not affect viral load or CD4 in participants that got infected, in south africa the same thing was used plus a 2 component gp120 protein subunit vaccine with adjuvant but stopped due to inefficacy 5 years later

elite controllers

they are infected but control their infection without treatment, they produce highly potent antibodies that neutralize a wide range of HIV isolate broadly neutralizing antibodies, most ppl with HIV develop non-neutralizing antibodies, induction of these antibodies is a major goal of many HIV vaccines

what are alternative approaches to inducing broadly neutralizing antibodies by vaccination?

antibody-mediated prevention so just giving ppl broadly neutralizing antibodies, manufacturing monoclonal antibodies that act as bnAbs and give them directly to people at risk of infection, trails ongoing, pediatric treatment, PrEP or breastfeeeding

shock + kill approach to curing HIV?

this is when you try to kick antiretroviral particle to get rid of it, the shock element wakes up the reservoir and kills the infected cells, a drug will deliver a shock that activates latent virus to start replicating again, infected cells can now be seen by the immune system, ART will prevent uninfected cells from becoming infected

what are the main takeaways when it comes to HIVÙ?

every antiviral immune mechanism leads to a viral counter meausre which triggers an immune counter-counter measure, viruses shape our immune system and our genome and antiviral immunity is unique because viruses hide inside cells via MHCI, CTLs, NK cells, IFNs and viral latency, immune responses msut be strong enough to clear virus bit not so strong that it harms you , timing is really important as the viral infection outcome is determined by kinetics of virus, innate and adaptive response, the winner determines if its acute or chronic and mild or severe, early treatment leads to better outcomes like for HIV

the reservoir problem

for chronic viruses the immune system can suppress but rarely eliminate, virus hiding in a form the immune system cant detect, solving this is the key to curing chronic viral infections

how is bacteria classified?

by morphology, gram stain characteristics (gram positive so one cell membrane vs gram negative so two cell membranes), also the preffered atmospheric growth conditions are important so aerobic (strict need for oxygen vs anaerobic)

anaerobic bacteria

obligate ones grow only in absence of oxygen so they are killed by oxygen but facultative ones can use oxygen if present but can also grow without it

capsule/slime layer of bacteria

its sugar coated which our immune system is bad at handling, its the outermost layer of the bacterium so in different situations it will form a capsule, slime layer or biofilm, a loose mesh of secreted polyssacharides (some protein) and its important for survival in the host, its a major virulence factor, it protects bacteria from immune responses by escaping phagocytosis, hiding the antigenic surface or it resembles the host cause glycans are shared by a capsule layer and a host, it acts as a barrier to toxic hydrophobic molecules like detergents and it promotes adherence to other bacteria and to host tissue, a plaque is formed by grouping bacteria on your teeth

flagella

ropelike propellers composed of the helically coiled protein flagellin, its responsible for motility toward food and away from toxins, it expresses antigenic and strain determinants

pili (fimbriae)

composed of protein subunits that form protein filaments, it promotes adherence to other bacteria and to the host, it plays a role in conjugation (transfer of DNA between cells), its also called adhesiins, lectins, evasins and aggressins, they are important virulence factors that cause damage and are named after the damage they cause (ex: e.coli adhesin allows colonization and infection of the urinary tract)

gram positive bacteria

makes up a thick peptidoglycan layer made of polymers of sugars and amino acids, it contains teichoic and lipoteichoic acids, it only makes one membrane and there is no periplasmic space

gram negative

thin peptidoglycan layer, second membrane that contains LPS making a TLR4 lgand and endotoxin, periplasmic space between membranes containing enzymes, transport and cell wall proteins

colonization (good)

this is when the immune system actively tolerates commensal bacteria, bacteria is present on/in the host without causing disease, host immune system actively tolerates the bacteria, the mucosal Tregs suppress inflammatory response to commensals, secreted IgA will undergo immune exclusion without inflammation, the epithelial barrier will create physical separation from the immune system and anatomical compartmentalization will result in bacteria restricted to surfaces where they cause no harm

when does infection occur?

when there is a barrier breach so the bacteria crosses epithelial/mucosal surfaces ending up in the bloodstream and potentially causing sepsis, immune compromise means the host cant contain colonizing bacteria, microbiome disruption means dysbiosis allows overgrowth and acquisition of virulence factors means commensal gains pathogenic potential,

why are bacteria challenging for the adaptive immune system?

most bacteria surface antigens are polysaccharides which are T cell independent antigens, they cant be presented on MHC so there is no direct T cell recognition, this activates B cells directly leading to T independent responses, predominantly IgM limited class switching and no immunological memory, bacteria proteins including exotoxins lead to T cell dependent antigens and better adaptive responses, against polyssaccharide antigens this leads to innate immunity dominating and against proteins antigens like exotoxins and flagellin this means adaptive immunity can be recrutied

vaccine design

want to overcome the polyssacharide problem by conjugating with a protein antigen

complement activation

this is an innate immune system response that can take place through the alternative pathway with spontaneous C3b deposition on bacterial surfaces where no antibody needed, lectin pathway where MBL binds bacterial carbs leading to C3b deposition or the classical pathway where antibody dependent IgM and IgG are the most efficient

opsonization and phagocytosis

this is when C3b leads to CR1/CR3 on phagocytes which enhances phogocytosis, IgG leads to FcyR on phagocytes that also enhances phagocytosis or IgM activates complement leading to C3b deposition which leads to phagocytosis

anaphylatoxins (C3a, C5a)

this resutlts in mast cell degranualtion causing vasodilation and increased permeability or neutrophil + macrophage recruitment amplifying response

neutrophil killing

phagocytosis causes oxidative burst leading to ROS/RNS, degranulation leading to antimicrobial peptides and lysozyme or NET formation trapping extracellular bacteria

IgG, IgA and IgM

they result in neutralization of toxins and adhesins, opsonization leading to phagocytosis via FcyR and complement activation

Th17 cells

secrete Il-17 which leads to CXCL8 production and neutrophil recruitment and IL-22 which leads to epithelial antimicrobial peptide production which is critical at mucosal surfaces against extracellular bacteria

immune responses to intracellular bacteria

this bacteria survives and replicates inside host cells shielded from circulating antibodies, complement and extracellular phagocytes, the immune system has to either activate infected cells to kill bacteria internally where MHC II leads to CD4 T cell activation which activates IFNy leading to macrophage activation, this kills infected cells by releasing bacteria for extracellular clearance so MCH I leads to CTLs being producing killing infected cells

complement lysis

this is usually not good enough to kill bacteria cause if it did it would release all toxins bacteria has inducing a huge immune response that is harmful to us, gram(+) bacteria has a thick peptidoglycan wall that physically blocks MAC insertion, gram(-) bacteria with long O-antigen is the outermost part of LPS and MAC cant reach it, for encapsulated bacteria, capsule prevents C3b deposition, opsonization leads to phagocytosis more important than direct lysis for most bacteria and better for us

endotoxin

structural component of gram (-) bacteria that drives systemic inflammation, only gram (-) bacteria produce it and its a structural component, it is released when bacteria die and lyse, divide by shedding outer membrane vesicles and are killed by antibiotics

exotoxin

this is a secreted bacterial proteins which targets damage to the host

how can LPS trigger immune response?

it can triggers an innate response by triggering the complement cascade or it binds to TLR4 on monocytes and other cells to trigger an inflammatory response or it triggers an adaptive one by binding to TLR4 on B cells to trigger a humoral response without the need of helper cells (because LPS is a T cell independent type 1 antigen it elicits polyclonal B cell activation and creates no generation of memory B cells so there is no affinity maturation or class switching

low dose endotoxin

this can prime the immune response against gram (-) bacteria and lead to appropriate immune responses, this systemic distribution of endotoxin can be deadly

endotoxemia

the presence of endotoxins in the blood

sepsis

an exaggerated, systemic inflammatory response that could be life-threatening if not controlled

local infection

macrophages are activated in the tissue, this leads to local secretion of TNF-a, immune activation in the tissue, phagogcytic clearance of bacteria and local vessel occlusion

systemic bacterial infection

macrophages are activated in the liver and spleen, secretion of TNFa into the bloodstream leads to a cytokine storm, this causes systemic edema (endothelial activation and dysfunction, leakage), decreased blood volume causing vessel collapse, disseminated intravascular coagulation and multiple organ failure

exotoxins

proteins actively produced by gram (+) and gram (-) bacteria or released during lysis, they are highly potent, cause damage to the host by destroying cells and disrupting normal cellular metabolism, they can be classified via targets (neurotoxins for brain and cardiotoxins for the heart)

immune defense against exotoxins

exotoxins are proteins that are T cell dependent antigens where immunological memory is possible but they are so toxic that they are fatal before the immune system can mount a defense, antitoxin antibodies are injected to provide passive immunity and many vaccines target exotoxins like the tetanus toxoid vaccine

superantigens

they are a special group of exotoxins, they dont need to be displayed in an immune synapse and can engage non specifically, superantigens are a special group of exotoxins, sequence and 3D structure is conserved among different superantigens and the function is similar as they undergo nonspecific activation of T cells (ex: toxic shock syndrome is caused by S.aureus enterotoxin B) which can trigger life-threatening autoimmune responses by stimulating strong cytokine response

typhoid

a common bacterial disease that is spread through fecal-oral transmission, only human to human transmission, its a systemic infection when in combination with salmonella which is basically a more toxic version of food poisoning bacteria, its gram negative, antibiotic treatment reduces death rate to 1% but drug resistance exists, there is a 10-30% death rate when untreated

typhoid symptoms (week 1)

its initially asymptomatic then you get gradual rise in temperature, malaise, headache and cough, bloody nose in 25% of cases, abdominal pain, adult constipation while children and HIV+ adults get diarrhea