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1

Different routes of entry of microbes

Microbes can enter the host by breaching epithelial surfaces, inhalation, ingestion, or sexual transmission.

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TABLE: Routes of Microbial Infection

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Routes of entry of microbes:

GI tract:
Denfenses, mechanisms of microbial entry

Most gastrointestinal pathogens are transmitted by food or drink contaminated with fecal material. When hygiene fails, diarrheal disease becomes rampant.

GI tract has local defenses:
- Acidic secretions kill many organisms
- Viscous mucus layer covers the gut, protecting epithelium
- Pancreatic enzymes and bile detergents can kill enveloped viruses
- Defensins are produced by GI epithelium
- IgA antibodies are produced in MALT 
- Peristalsis 
- Normal gut flora

GI infections occur when local defenses are circumvented by a pathogen or when they are so weakened that even normal flora produce disease.  

Norovirus is a non-enveloped virus resistant to many defenses

Enteropathogenic pathogens may establish symptomatic GI disease through these mechanisms:
- Adhesion and local proliferation: binding intestinal epithelium and multiplying in mucous layer, elaborating potent exotoxins (e.g. Vibrio cholerae, enterotoxigenic E. coli)
Adhesion and mucosal invasion: Invasion of intestinal mucosa / lamina propria, with ulceration, inflammation, hemorrhage --> dysentery (e.g. Shigella, Salmonella enterica, Campylobacter jejuni)
- 'Hijacking' of the host pathways of antigen uptake: M cells of Peyer's patches, responsible for uptake and delivery of antigen to lymphoid cells, take up organisms through the same pathway (e.g. Poliovirus)

Some foodborne organisms (e.g. S. aureus) cause disease without causing infection of the host, just by elaborating exotoxins in the food.

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Routes of entry of microbes:

Respiratory tract:

Inhaled microorganisms of any kind, mainly in small (< 5 um) dust or aerosol particles, are carried into alveoli, phagocytized by alveolar macs and neuts, causing inflammation.

Microorganisms evade host defense in several ways:
- Viruses attach and enter epithelial cells in lower resp tract and pharynx (e.g. influenza virus has hemagglutinins that bind epithelial cells --> endocytosed virus --> replication --> promotes superinfection by bacteria (S. pneumoniae, S. aureus)
- Bacteria can release toxins that impair ciliary activity (e.g. Haemophilus influenzae, M. pneumoniae, Bordetella pertussis)
- Primary resistance to phagocytosis (e.g. Mycobacterium tuberculosis)

Mucociliary apparatus: Composed of mucus layer and ciliated columnar epithelium on mucosa; important defense mechanism 

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Routes of entry of microbes:

Urogenital tract

Urine is sterile, and urinary tract is protected from infection by regular emptying during micturition.  Urinary pathogens (e.g. E. coli) almost always gain access via urethra and must adhere urothelium to avoid being washed away.

Women have 10 times as many UTIs as men due to shorter distance between bladder and skin.

Obstruction of urinary flow or reflux of urine compromises normal defenses and increases susceptibility to UTIs.

 

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Routes of entry of microbes:

Skin

Keratinized epidermis provides a mechanical barrier against infection and produces antimicrobial fatty acids and defensins that are toxic to bacteria.  

Most skin infections are initiated by mechanical injury of the epidermis. 
Some fungi (e.g. dermatophytes) can cause superficial infections of the stratum corneum, hair, and nails

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Routes of entry of microbes:

Vertical transmission

Common mode of transmission of certain pathogens, can occur through several routes:

1. Placental-fetal transmission: Most likely when mother infected with a pathogen during pregnancy; Resulting infections interfere with fetal development, and are based on age of the fetus (e.g. Rubella)

2. Transmission during birth: Causd by contact with infectious agents during birth (e.g. gonococcal and chlamydial conjunctivitis)

3. Postnatal transmission in maternal milk (e.g. cytomegalovirus, HIV, hepatitis B)

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Spread and dissemination of microbes within the body

While some disease-causing microorganisms remain localized to the initial site of infection, others have the capacity to invade tissues and spread to distant sites via the lymphatics, the blood, or the nerves.

Some pathogens secrete enzymes that break down tissues, allowing them to advance (e.g. S. aureus secretes hyaluronidase) to LNs and lymphatics

Certain viruses (e.g. Rabies, polio, varicella) spread to CNS by infecting peripheral nerves

Most common route of spread is through bloodstream.  Many organisms are either transported free in plasma or within leukocytes

Consequences of blood-borne spread of pathogens vary widely depending on virulence of the organism, magnitude of infection, seeding pattern, and host faactors such as immune status.

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Seven mechanisms by which microbes cross mucosal barrier systems

1. Endosomes and transcytosis via M cells

2. Intercellular junctions

3. Endosomes and transcytosis via other types of epithelial cells

4. Mucosa-associated dendritic cells

5. Migrating mucosa-associated lymphocytes

6. Migrating mucosa-associated macrophages

7. Mucosa-associated nerve endings

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Routes of entry and dissemination of microbes. To enter the body, microbes penetrate the epithelial or mucosal barriers. Infection may remain localized at the site of entry or spread to other sites in the body. Most common microbes (selected examples are shown) spread through the lymphatics or bloodstream (either freely or within inflammatory cells). However, certain viruses and bacterial toxins may also travel through nerves.

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Release of microbes from the body and transmission of microbes

Microbes use various exit strategies to get from one host from the next.  

Depending on location of infection, release may occur via skin shedding, coughing, sneezing, urine, feces, sex, insect vectors.

Shedding can be brief and during disease flares with some organisms.
Others (e.g. S. typhi) are shed for long periods by asymptomatic carriers.

Hardiness in environment varies by organism.  Bacterial spores, protozoan cysts, helminth eggs can remain viable in a cool,d ry environment from months to years.

Most pathogens are transmitted from person to person by respiratory, fecal-oral, or sexual routes.
- Respiratory viruses and bacteria are aerosolized in droplets when coughing.  Pathogens in large droplets (e.g. influenza) can travel only 3 feet from source.  Pathogens in small droplets (e.g. M. tuberculosis) can travel much longer distances.
- Enteric pathogens are spread usually by fecal-oral route; Foodborne (Vibrio, Shigella, Campy, Salmonella). Waterborne (Hepatitis A and E, polio, rotavirus). Helminths (e.g. hookworms) can shed eggs in stool that hatch as larvae that can penetrate the skin of the next host.
- STDs: Prolonged, intimate, mucosal contact 

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KEY CONCEPTS: How microorgansims cause disease

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 Host defenses against infection

The outcome of infection is determined by the virulence of the microbe and the nature of the host immune response, which may either eliminate the infection or, in some cases, exacerbate or even by the principal cause of tissue damage.

Host defenses include physical barriers, innate immunity, and adaptive immunity

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Immune evasion by microbes

Most pathogenic microbes have developed one or more strategies that allow them to evade host defenses.

Some examples:
1. Antigenic variation: Important to escape antibody-mediated defenses. Microbes can change their coats by expressing different surface antigens. Influenza viruses exhibit prominent antigenic drifts and shifts. 

2. Resistance to antimicrobial peptides: Peptides (defensins) produced by epithelial cells and some leukocytes are toxic to microbes by forming pores in their membranes.  These peptides also can augment anti-microbial immunity by inducing pro-inflammatory cytokines and chemokine production. Pathogens can become resistant to these peptides by changing net surface charge and membrane hydrophobicity, preventing peptide insertion.

3. Resistance to killing by phagocytosis: Many mechanisms developed to avoid phagocytosis (e.g. carb capsule on bacteria surface, special sialic acid-containing capsule of E. coli won't bind C3b, S. aureus expresses protein A, which binds Fc of antibodies)

4. Evasion of apoptosis and manipulation of host cell metabolims: Some viruses produce proteins that interfere with apoptosis and/or autophagy, buying them time to replicate, enter latency, or transform host cells. 

5. Resistance to cytokine-, chemokine-, and complement-mediated host defense: Viruses may express factors that interfere with JAK/STAT pathway, or inhibit dsRNA-dependent protein kinase (PKR), a mediator of IFN

6. Evasion of recognition by CD4+ helper T cells and CD8+ cytotoxic T cells: Viruses can alter MHC I proteins and/or MHC II proteins

7. Immunoregulatory mechanisms to downregulate anti-microbial T cell responses: Antigen-specific T cells lose potency during chronic viral infections (i.e. T cell exhaustion) - chronic feature of HIV, hep C, hep B

8. Latent infection: Ultimate means of avoiding immune system. 

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Antigenic drift and antigenic shift definitions

Antigenic drift: Minor changes in DNA/RNA leading to different surface proteins, prompting immune responses and future immunity (e.g. hemagglutinin (HA) and neuraminidase (NA))

Antigenic shift: More major change in virus DNA/RNA. This usually occurs from two strains of virus crossing and mutating to make a new subtype. Three ways this can happen:
1. An animal (pig) is infected with a human flu and another (bird) flu. These mix and mutate to make a new flu that can infect humans
2. A strain of bird flu passes to humans without any genetic change.
3. Bird flu passes to another animal (pig) and then is passed to humans without genetic change.

 

These occur frequently in influenza viruses

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TABLE: Mechanisms of antigenic variation

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An overview of mechanisms used by viral and bacterial pathogens to evade innate and adaptive immunity.

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KEY CONCEPTS: Immune evasion by microbes

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Infectious agents establish infection and damage tissues by three mechanisms:

1. They can contact/enter host cells and directly cause cell death or changes in cellular metabolism 

2. They may release toxins that kill cells at a distance, release enzymes that degrade tissue, or damage blood vessels and cause ischemic necrosis

3. They can induce host immune responses that cause additional tissue damage

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Mechanisms of viral injury

Viruses can enter host cells and replicate.  

Viruses show a predilection (i.e. tropism) for certain cells and not others

A major determinant of tissue tropism is the presence of viral receptors on host cells.

Once viruses enter cells, they can damage and kill the cells by these three mechanisms:
1. Direct cytopathic effects: Some produce toxic enzymes and proteins, and some prevent host macromolecule synthesis.  Some viruses initiate death receptor apoptosis pathway, and some lead to unfolded protein accumulation, some encode pro-apoptotic proteins.

2. Anti-viral immune responses: Cytotoxic T lymphocytes can cause tissue injury

3. Transformation of infected cells: Oncogenic viruses stimulate cell growth and survival

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Mechanisms by which viruses cause injury to cells.

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Mechanisms of bacterial injury:

Bacterial virulence

Bacterial damage to host tissues depends on the ability of the bacteria to adhere to host cells, to invade cells and tissues, or to deliver toxins.

Mobile genetic elements such as plasmids and bacteriophages can transmit functionally important genes to bacteria, including genes that influence pathogenicity and drug resistance. 

Quorum sensing: Bacteria coordinately regulate gene expression in a large population, so they can acquire complex virulence properties

Biofilms: Communities of bacteria in which the organsims live in a viscous extracellular layer of polysaccharides that adhere to host tissues or objects (e.g. dog bowls). Biofilms enhance adherence to host tissues and increase virulence by protecting microbes from immune effecto rmechanisms

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Mechanisms of bacterial injury:

Bacterial adherence to host cells

Adhesins: bacterial surface proteins that bind bacteria to host cells or ECM

Pili: filamentous proteins on bacterial surface that act as adhesins

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Mechanisms of bacterial injury:

Virulence of intracellular bacteria

M. tuberculosis activates the alternative complement pathway, is opsonized by C3b, and then binds CR3 receptors on macrophages, enters them, and replicates inside.  

Once inside a cell, Listeria monocytogenes modifies actin cytoskeleton to promote spreading of organism to neighboring cells

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Mechanisms of bacterial injury:

Bacterial toxins

Endooxins: Components of the bacterial cell
Exotoxins: Secreted by the bacterium

Bacterial endotoxin is a LPS in the outer membrane of gram negative bacteria that stimulates host immune responses and injures the host.
Lipid A anchors LPS to host cell membrane, inducing inflammatory response. High levels of endotoxin play a part in septic shock, DIC, ARDS through induction of TNF, IL-1, IL-12

Exotoxins are secreted bacterial proteins that cause cellular injury and disease. Different categories include:
- Enzymes (e.g. proteases, hyaluronidases, coagulases, fibrinolysins)
- Toxins that alter intracellular signaling or regulatory pathways: Most have an active subunit with enzymatic activity and a subunit that binds receptors and delivers A subunit into cytoplasm
- Neurotoxins (e.g. by C. botulinum and C. tetani): Inhibit release of NTs, causing paralysis. A domains interact with proteins involved in NT secretion at synapses
Superantigens: bacterial toxins that stimulate very large number of T lymphsby binding TCR, leading to massive T-lymph proliferation and cytokine release

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KEY CONCEPTS: Host damage

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Spectrum of inflammatory responses to infection

1. Suppurative (purulent) inflammation
- Increased vascular permeability and leukocyte infiltration (mainly neuts)
- 'pyogenic' bacteria release chemoattractants to pull neuts in
- Mostly extracellular, gram-positive cocci and gram-negative rods
- Tiny microabscesses to entire lung lobes of pneumonia can be involved

2. Mononuclear and granulomatous inflammation
- Common feature of all chronic inflammatory processes
- When they develop acutely, they are often in response to viruses, intracellular bacteria, or intracellular parasites
- May include mostly lymphocytes, plasma cells, or macrophages
Granulomatous inflammation: usually evoked by bugs that resist eradication and stimulate T-cell immunity (e.g. M. tuberculosis, Histoplasma capsulatum) - epithelioid macs, multinucleated giant cells

3. Cytopathic-cytoproliferative reaction
- Usually produced by viruses, cell necrosis and/or proliferation
- Sparse inflammatory cells
- Some viruses (e.g. herpes, adenovirus) cause make inclusion bodies

4. Tissue necrosis
- C. perfringens and others secrete powerful toxins that cause rapid and severe gangrenous necrosis; tissue damage is the prominent feature.

5. Chronic inflammation and scarring
- Chronic inflam can lead to scarring or complete healing
- Dense fibrous septae seen with scarring

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TABLE: Spectrum of inflammatory responses to infection

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Special techniques for diagnosing infectious agents

The gold standards for diagnosis of infection are culture, biochemical/serologic identification, and in some cases, molecular diagnosis. 

Some organisms can be seen on H&E (e.g. inclusion bodies from CMV and herpes simplex, bacterial clumps, Candida, protozoans, helminths).  Others require various special stains.

Nucleic acid amplification tests (e.g. PCR) and transcription-mediated amplification, are increasingly being used for rapid microbe IDing.

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TABLE: Special techniques for diagnosing infectious agents