10.1 From Notes - Emerging Infections and Zika Virus (ZIKV)

Emerging Infections

• New infections are emerging at a potentially unprecedented rate, with over 40 arising in a single generation.
• Some originate in animals before spreading to humans.
• Zika virus (ZIKV) was first found in rhesus monkeys in Uganda (1947) and mosquitoes (1948).
• The first human cases of ZIKV were reported in Uganda and Tanzania in 1952 and in Nigeria in 1953.
• A major ZIKV outbreak occurred on Yap Island in Micronesia in 2007.
• The number of sexually transmitted ZIKV cases has increased, where transmission occurs through semen, sperm, and vaginal fluid.
• Semen can contain infectious ZIKV for up to 6 months after symptom onset.
• ZIKV can be transmitted from mother to child during pregnancy or delivery.
• ZIKV is neurotropic and can cause miscarriage, fetal death, microcephaly, and ocular disorders.
• As of September 6, 2017, the CDC reported 231 symptomatic ZIKV cases in the United States and 554 in U.S. territories.
• Destruction of mosquito breeding sites is the most effective measure to limit ZIKV spread.
• Additional prevention strategies include limiting travel to endemic areas, preventing mosquito access to homes, using insect repellents, and wearing protective clothing.
• Public health agencies are concerned about the potential reversion of some slowly spreading or initially isolated infections (e.g., AIDS, Ebola) to more rapidly spreading variants.
• The WHO has developed a list of emerging viral diseases needing urgent attention due to their epidemic potential.
• Diminished insecticide use and increased global warming contribute to the spread of insect vectors.

Microorganisms and Humans: A Dynamic Relationship

• The human body provides a hospitable environment for microorganisms due to sufficient nutrients.
• Humans have commensal, mutualistic, and pathogenic interactions with microorganisms.
• Many microorganisms reside within the normal microbiome without causing disease.
• Beneficial homeostasis with normal flora is maintained by physical barriers and other mechanisms.
• Gut microbiota aids in digesting food, inhibiting pathogenic microorganisms, and producing usable metabolites like vitamin K and B vitamins.
• Opportunistic microorganisms can cause infection if protective barriers or defenses are weakened.
• True pathogens have developed mechanisms to circumvent the body's defenses.

Microorganisms and Infections

• Clinical infectious disease results from pathogenic microorganisms.
• Microorganisms are classified based on morphology and life cycles.
• Disease-causing groups share properties related to clinical disease.
• Infection occurs when pathogenic microorganisms colonize and multiply in a host, causing damage.

Process of Infection

• The process of infection includes colonization, invasion, multiplication, and dissemination.
• Colonization involves adherence to tissue through surface receptors.
• Invasion allows the microorganism to penetrate surrounding tissue.
• Multiplication occurs rapidly in the warm and nutrient-rich host environment.
• Viruses replicate within infected cells, and some bacteria are intracellular pathogens.
• Successful spreading requires virulence factors such as adhesion molecules, toxins, and the ability to evade immunity.
• Biofilms, formed by mixed species of microorganisms, can anchor to surfaces and resist immune defenses and antibiotics and are associated with chronic infections.
• Stable bacterial colonization requires adhesion, often mediated by pili (fimbriae), surface glycoproteins, or complement-related receptors.
• E. coli uses pili-associated adhesins for binding to specific glycoproteins.
• Invasion leads to confrontation with host defense mechanisms like complement, antibodies, and phagocytes. Evasion of these defenses can result in bacteremia, viremia, fungemia, and sepsis.
• Bacteria can protect against phagocytosis by producing toxins that destroy phagocytic cells and extracellular enzymes that digest complement components, clotting factors, immunoglobulins, cytokines, and antimicrobial peptides.
• Some intracellular microorganisms may enter a latency phase within infected cells until reactivation occurs (e.g., herpes simplex virus, CMV, tuberculosis).

Clinical Infectious Disease

• Initial symptoms of infection are typically fatigue, malaise, weakness, and loss of concentration.
• Generalized aching and loss of appetite are common symptoms of infection.
• Fever is a regulated increase in body temperature controlled by the hypothalamus in response to pyrogens.
• Pyrogens stimulate prostaglandin synthesis.
• Fever is considered a beneficial host-defense response.

Factors Influencing the Capacity of a Microorganism to Cause Disease

• Communicability refers to the ability to spread and cause disease.
• Immunogenicity refers to the ability to induce an immune response.
• Infectivity refers to the ability to invade and multiply in the host.
• Mechanism of action refers to how the microorganism damages tissue.
• Pathogenicity refers to the ability to produce disease, depending on communicability, infectivity, tissue damage, and virulence.
• Portal of entry refers to the route of infection (e.g., direct contact, inhalation, ingestion, bites).
• Toxigenicity refers to the ability to produce soluble toxins or endotoxins, influencing virulence.
• Virulence refers to the capacity to cause severe disease (e.g., measles virus [low] vs. rabies virus [high]).

Classification of Infectious Diseases by Prevalence and Spread

• Endemic: constant rate of infection in a population.
• Epidemic: number of new infections greatly exceeds the usual number.
• Pandemic: epidemic spreading over a large area (e.g., continent or worldwide).

Notification of Infectious Diseases

• The CDC has a National Notifiable Diseases Surveillance System to monitor, control, and prevent the spread of disease
• STIs were among the most common reportable diseases in 2015.

Transmission of Infection

• Microorganisms can be transmitted directly from person to person through contact.
• Direct transmission includes touching, kissing, sexual contact, droplet spread, and transplacental transmission.
• Indirect transmission occurs via contaminated materials (e.g., towels, food) or vectors.
• Iatrogenic transmission results inadvertently from medical procedures.
• Fecal-oral transmission occurs through ingestion of substances contaminated by feces.
• Zoonotic infections can be directly transmitted from animals (e.g., rabies) or indirectly via vectors.

Classes of Infectious Microorganisms

• Infectious microorganisms can be bacterial, fungal, parasitic, protozoal, or viral.

Infectious Bacteria

• Bacteria are prokaryotic unicellular microorganisms.
• Bacteria are divided into groups like "true bacteria," filamentous, spirochetes, mycoplasma, rickettsia, and chlamydia, and can be gram-positive or gram-negative.
• Gram stain differentiates bacteria based on cell wall structure.
• Many bacteria have specialized surface structures like pili and flagella that promote adhesion and tissue invasion.
• Pili can express adhesins that bind to host cell components.
• Bacteria produce a variety of toxic molecules that can kill host cells, disrupt tissue, and affect inflammation.
• Exotoxins are proteins released during growth with specific or broad effects and are classified by their mode of action (Type I, II, III).
  • Superantigens (Type I) cause overproduction of cytokines , membrane-damaging toxins (Type II) , and A-B toxins (Type III) that require binding and active components.
  • A-B toxins include botulinum toxin, tetanus toxin, diphtheria toxin, and cholera toxin.
• Endotoxins (lipopolysaccharide [LPS]) are part of the gram-negative bacterial cell wall and are released during lysis.
  • Lipid A is responsible for the toxic effects, leading to inflammation, fever (pyrogenic bacteria), vasodilation, decreased oxygen delivery, cardiovascular shock, activation of the coagulation cascade, and release of TNF-α.
• Inflammatory and immune responses to bacterial infection can cause tissue damage through excessive cytokine production and activation of the complement system.
• Hypersensitivity reactions (Type II and III) can occur.
• Cell-mediated responses against intracellular bacteria can also damage surrounding healthy tissue.
• Bacteria employ various evasion mechanisms against immune and inflammatory systems, which include rapid progression which can overwhelm the initial immune response.
• Protection against phagocytosis can involve antiphagocytic capsules, toxins that kill phagocytes, and enzymes that damage phagolysosomes.
• Some bacteria can neutralize the toxic environment of the phagolysosome or escape from it.
• Blocking recognition of bacterial antigens can occur through coating with host proteins or capsules resembling host components, and antigenic variation allows pathogens to alter surface antigens.
• Resistance to complement is achieved through capsules, degradation of complement factors, or use of bacterial regulatory proteins.
• Some bacteria can suppress immune responses by blocking T cells or impairing inflammatory signals.
• Staphylococcus aureus (S. aureus) is a commensal and opportunistic pathogen with numerous virulence factors contributing to invasive infection and antibiotic resistance.
• S. aureus can cause a range of infections depending on the strain and toxins produced.
• S. aureus has developed defenses against antibody and complement-mediated phagocytosis, and it inhibits neutrophil functions and modifies B- and T-cell responses.

Infectious Fungi

• Fungi are eukaryotic microorganisms with thick, rigid cell walls that grow as molds (mycelium), yeasts, or be dimorphic.
• Fungal infection is called mycosis.
• Pathogenic fungi can be from the environment (transmitted by inhalation or wound contamination) or exist as human commensals causing superficial mycoses.
• Human-to-human transmission is primary for dermatophytes causing skin, nail, and hair infections.
• Systemic mycoses often start as pulmonary infections after spore inhalation.
• Opportunistic fungal infections are common in immunocompromised individuals.
• Diagnosis involves microscopic observation and culture.
• Fungi have polysaccharide surface molecules that promote adhesion to epithelial tissue via host receptors like TLRs and mannose receptors.
• Some fungi produce toxins that promote infection, evade immune responses, or cause cancer.
• Fungi can secrete enzymes that damage tissue and initiate pathogenic inflammatory responses, including hypersensitivity reactions.
• The immune response to fungal infections involves cell-mediated immunity.
• Hyperinflammatory responses can enhance fungal virulence, and persistent infections can lead to granuloma formation.
• Pulmonary exposure can also elicit IgE responses and allergic pneumonitis.
• Fungi employ various evasion mechanisms, where many are dimorphic, adapting to the host environment by changing morphology.
• Encapsulated yeast cells are more resistant to phagocytosis by masking PAMPs.
• Some fungi produce toxic metabolites (e.g., gliotoxin) that inhibit phagocytosis and suppress inflammation.
• Some fungi can survive in phagocytes and resist lysosomal destruction, even replicating within phagosomes or producing proteins that inhibit lysosomal enzymes.
• Altered antigen expression can provide protection, and some yeasts stimulate the production of immunosuppressive cytokines.
• Candida albicans (C. albicans) is a common cause of fungal infections, residing in the skin, GI tract, mouth, and vagina.
• Local defenses, including the bacterial microbiome, produce antifungal agents.
• In healthy individuals, infection remains localized.
• C. albicans can form biofilms on medical devices and undergoes morphologic changes between yeast and hyphal forms.
• It expresses diverse adhesion molecules and can evade the immune response.

Infectious Parasites and Protozoans

• Parasites establish a symbiosis where they benefit at the expense of the host, ranging from unicellular protozoa to large worms (helminths).
• Helminths include nematodes, flukes, and tapeworms.
• Parasite invasion can be extracellular or intracellular, involving adherence and breakdown of connective tissue and basement membranes to enter the circulatory system.
• Some parasites are obligatory intracellular parasites.
• Toxins are less prevalent in parasitic diseases compared to bacterial ones.
• Some parasites produce toxins that disrupt cell membranes.
• Tissue damage is often secondary to enzyme release (proteases, phospholipases) aiding invasion.
• Damage from large multicellular parasites can be due to accumulation in tissue or host immune responses.
• Infestations can lead to nutrient malabsorption, anemia, or lymphatic blockage (e.g., elephantiasis).
• Parasitic infections can also cause tissue damage through exacerbated inflammation or hypersensitivity reactions.
• Parasites employ various evasion mechanisms.
  • Some (e.g., Leishmania) are obligate intracellular organisms of macrophages, using complement for entry and various mechanisms for survival within.
  • Some produce toxins that prevent phagosome-lysosome fusion or release enzymes that disrupt phagocyte membranes.
  • Some escape from the phagosome and grow in the cytoplasm.
  • Blocking recognition of parasitic antigens can occur by coating themselves with host proteins or through antigenic variation.
• Malaria, caused by Plasmodium, is a significant global infection with complex immune evasion strategies involving different life cycle stages.
• The parasite traverses cells, modulates cytokine profiles, avoids splenic phagocytes, and uses stage-specific antigen variation.

Infectious Viruses

• Viruses are simple microorganisms consisting of nucleic acid (RNA or DNA, single- or double-stranded) protected by a protein capsid, sometimes surrounded by an envelope.
• Viral diseases are the most common human afflictions.
• Viral pathogens directly destroy or damage cells during replication.
• Viruses are obligatory intracellular parasites, and viral invasion involves binding to host cell receptors, followed by entry through fusion or endocytosis.
• Replication involves using the host cell's machinery to produce new viral components, which are then assembled and released.
• Some viruses can establish latency.
• Viruses rarely produce toxins, but some products important for their life cycle can indirectly cause cellular destruction.
• Rotavirus NSP4 is an exception, acting as an enterotoxin.
• Most symptoms of viral infection are due to the host's inflammatory response; however, severe cellular effects can result from infected cell destruction.
• Hepatitis viruses can provoke immune responses that damage liver cells.
• Viruses employ various evasion mechanisms, where rapid progression allows them to spread before an effective adaptive immune response develops.
• Some can interfere with innate immunity by blocking recognition of viral substances or TLR signaling.
• Blocking recognition of viral antigens can occur through enveloped viruses masking their capsid with the host cell membrane or by coating with normal host proteins (e.g., HCV with lipoproteins).
• Some viruses increase antigenic diversity through frequent translational errors (e.g., HIV).
• Some induce immunosuppression of T cells (e.g., measles, HIV).
• Some interfere with antigen processing and presentation by MHC class I molecules (e.g., herpesviruses, retroviruses).
• Some produce molecules that mimic or block complement components.
• Influenza virus is a highly infectious ssRNA virus transmitted through aerosols, causing a range of symptoms and potentially leading to pneumonia.
• Viral surface antigens (hemagglutinin [HA] and neuraminidase [NA]) are key to infection and targets for immunity.
• Antigenic drift and shift contribute to new influenza variants.
• Neuraminidase inhibitors can lessen symptom severity.
• Pathogenicity is influenced by viral factors and the intensity of the host's immune response, including cytokine production.

Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS)

• HIV causes AIDS, a secondary immune deficiency characterized by the depletion of CD4+ Th cells, making individuals susceptible to opportunistic infections and malignancies.
• HIV is a retrovirus.
• HIV-1 is the major virulent variant, while HIV-2 is less virulent and mostly found in western Africa.
• The HIV virion contains two RNA copies, reverse transcriptase, integrase, and a capsid enclosed in an envelope with gp41 and gp120 envelope proteins.
• The HIV life cycle begins with attachment to CD4 and chemokine receptors on target cells (primarily Th cells) via gp120.
• Fusion, reverse transcription of RNA to DNA, integration of viral DNA into the host genome (provirus) by integrase, transcription, translation of viral proteins, assembly, and budding of new virions follow.
• The major immunologic finding in AIDS is a significant decrease in CD4+ Th cell numbers due to direct killing of infected cells, apoptosis of uninfected cells, and killing by CD8+ T cells.
• Clinical manifestations of HIV are staged based on CD4 cell counts.
• Stage 0 is the first 180 days after infection, while stages 1-3 reflect disease progression.
• Stage 3 (AIDS) is defined by low CD4 counts or the development of AIDS-related opportunistic infections.
• Early infection may involve acute viral syndrome-like symptoms.
• The presence of anti-HIV antibody indicates infection.
• Treatment involves highly active antiretroviral therapy (HAART), a combination of drugs targeting different stages of the HIV life cycle.
• HAART includes reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and entry inhibitors.
• The goals are to reduce viral load, reduce morbidity, prolong survival, and prevent transmission.
• Antiretroviral therapy does not cure HIV/AIDS because the viral genome integrates into the host cell DNA, creating reservoirs.
• The primary reservoir is long-lived CD4+ memory T cells.
• Developing an effective HIV vaccine is challenging due to the virus's high rate of mutation and antigenic diversity.
• Pediatric HIV infection can occur through placental passage, contact with infected fluids during birth, or breastfeeding.
• Untreated pediatric HIV can lead to progressive encephalopathy.

Countermeasures Against Pathogens

• Antibiotic resistance is a growing concern, driven by factors like overuse and misuse of antibiotics. In addition, emerging resistance mechanisms, including resistance to last-resort antibiotics like carbapenems and colistins, pose a significant threat. Pan-antibiotic resistant microorganisms have been identified.
• Antibiotic resistance can result from inherited processes and the spread of resistance genes through horizontal gene transfer, where common mechanisms include enzymatic inactivation, alteration of antibiotic target sites, bypassing metabolic steps inhibited by antibiotics, and efflux pumps.
• Active immunization (vaccines) aims to induce immunologic protection without causing disease with vaccines consisting of live attenuated organisms, killed microorganisms, inactivated bacterial toxins (toxoids), or subunit vaccines, and successful vaccines induce both humoral and cellular immunity.
• Passive immunization involves administering preformed antibodies.

Understanding Infectious Diseases: Mechanisms, Transmission, and Control

• Infection was the primary cause of death for most of human history.
• Modern public health initiatives like vaccines and antibiotics have been crucial in preventing and treating infectious diseases.
• The emergence of new infections, the re-emergence of old ones, and the development of antibiotic resistance continue to make infection a significant cause of illness and death.

Microorganism Classification and Disease Progression

• Microorganisms are classified based on different characteristics and life cycles.
• The incubation period is the time from initial exposure to the onset of symptoms, ranging from hours to years.
• The prodromal stage involves the occurrence of initial symptoms.
• Invasion is when the pathogen rapidly multiplies and spreads further, triggering inflammatory and immune responses and causing tissue damage.
• Convalescence is when the immune and inflammatory systems successfully eliminate the infectious agent.
• Fever is a hallmark of infectious disease caused by cytokines like interleukins 1 and 6, interferon, and tissue necrosis factor, which raise the thermal regulatory set point in the brain and peripheral tissues through prostaglandin synthesis.

Infection Occurrence

• Infection can occur when opportunistic organisms take advantage of broken protective barriers or weakened defense systems.
• True pathogens have developed ways to circumvent host defenses, and infection usually depends on having a sufficient number of microorganisms, which varies per pathogen.

Transmission

• Direct transmission occurs through contact with infected individuals, such as with fungal skin infections, scabies, or STIs.
• Indirect transmission happens through contact with contaminated materials, like food or commonly touched surfaces.
• Respiratory transmission is common for many viral diseases, including the cold, influenza, mumps, and measles.

Classes of Infectious Microorganisms

• All infectious microorganisms cause disease but differ in their mechanisms of invasion, reproduction, and size.
  • Bacteria: Bacterial pathogens produce toxins that can kill cells, disrupt tissue, or protect against host defenses. Excess toxins released during growth can have specific or broad effects; sufficient amounts of endotoxins can lead to fatal septic shock. The structure of the cell wall determines Gram staining characteristics: Gram-positive bacteria have thick, layered cell walls, while Gram-negative bacteria have a thin peptidoglycan layer. Gram stain characteristics help determine antibiotic sensitivity and treatment. Bacterial defenses include utilizing host inflammatory and immune responses to further infection and rapid progression to overwhelm the immune system. Some bacteria have evolved mechanisms to survive phagocytosis by macrophages, such as preventing lysosome-phagosome fusion, neutralizing lysosomal enzymes, or escaping the phagosome.
  • Infectious Fungi: Fungal cells contain organelles similar to human cells (mitochondria, Golgi, etc.), meaning their composition is alike, and fungi can be toxic to their host. Fungal invasion mechanisms include adhering to epithelial cell walls. Fungi cause tissue damage directly by secreting enzymes and indirectly through inflammatory responses. Pulmonary exposure to spores can cause an allergic response leading to excessive granulation of mast cells and potentially shock, and fungi have also evolved mechanisms to protect against phagocytosis.
  • Infectious Parasites and Protozoans: Parasitic organisms establish symbiosis where they benefit at the expense of the host, ranging from unicellular protozoa to large intestinal worms. Toxoplasma gondii is the most common parasitic infection in the US. Invasion often involves adherence to and breakdown of connective tissue and basement membranes; tissue damage is mainly caused by enzymes assisting invasion or by the accumulation of parasites, leading to loss of tissue function. Moreover, many parasites have mechanisms to block protective immune responses; malaria is a notable example.
  • Infectious Viruses: Viruses are very simple microorganisms lacking metabolic organelles. Many RNA viruses can alter host cell DNA, integrating their genetic information and transmitting it to daughter cells. Viruses typically do not produce toxins; their goal is adherence to target cells and invasion for reproduction. As obligatory intracellular pathogens, viruses hide and proliferate within cells, away from normal immune responses. Some viruses, like HIV, can infect and kill immune cells, leading to immunosuppression, where some viruses have an envelope that needs to be removed for invasion. The viral life cycle includes attachment to receptors, binding that triggers endocytosis, uncoating (if an envelope is present), replication, and release by exocytosis.

HIV as an Example

• HIV is a retrovirus that infects and depletes the immune system.
• Aggressive treatment with antiretroviral drugs has made AIDS a chronic and manageable illness.
• Therapeutic interventions target various stages of the HIV life cycle, including reverse transcriptase inhibitors, entry inhibitors, protease inhibitors, and integrase inhibitors (viral integration inhibitors).
• The goals of HIV therapy are to reduce viral load, reduce morbidity, prolong survival, and prevent transmission; even with treatment, individuals may have a shortened lifespan due to persistent immune activation, systemic inflammation, and drug toxicity, leading to other comorbidities.
• Pediatric HIV transmission has been reduced with prenatal antiviral therapy, neonatal prophylaxis, and avoidance of breastfeeding.
• Untreated children with HIV often develop opportunistic infections within the first year, and life expectancy is generally less than three years.

Safeguarding and Control

• Safeguarding populations from infectious diseases includes sewage removal and maintaining high-quality food and water.
• Lack of implementation or breakdown of these measures has led to the re-emergence of some infectious diseases, and control measures remain poor in many developing countries.

Antimicrobials

• Antibiotics are natural products that kill or inhibit the growth of microorganisms.
• Bactericidal antibiotics kill the organism, while bacteriostatic antibiotics inhibit growth until the organism is destroyed by the host's defenses.
• Antibiotic mechanisms of action include: inhibition of cell wall function or production, prevention of protein synthesis, blockage of DNA replication, and interference with folic acid metabolism.
• Vaccines induce active immunologic protection before exposure to a potentially debilitating or fatal infection.
• Mass vaccination programs have led to major improvements in global health, including the eradication of measles in the US (2000), smallpox (1979), and polio (1994).
• Complacency or resistance to immunization can cause disease resurgence, as seen with measles outbreaks.

Passive Immunotherapy

• Passive immunotherapy involves giving pre-formed antibodies to an individual.