Chapter 2 Vol. II: Barriers to Infection

B An Overview of infection and immunity A game of chess played by masters A more fitting metaphor to define the events pursuant to a viral infection would be a game of chess played by two masters. For each action, there follows a counteraction Virus particles must come in physical contact with permissive and susceptible cells for infection to occur, necessitating some disruption of the skin to allow access of the virus to live cells Even in mice with intact immune responses, viral movement from tissue to tissue means that the immune response is continually playing catch-up: as infection is controlled in the liver, infection of the skin appears All surfaces of the mammalian body where pathogens may enter are protected by defensive layers provided by fur, skin, and mucus, or are acidic environments Once these barriers are crossed and cells become infected, intrinsic cellular defenses including cell-autonomous responses, such as autophagy and cell suicide, are engaged Because the virus may reproduce faster than an infected cell can control it, the "professional" immune Adaptive response is also induced, beginning with the early Innate innate response ◦Created in ◦Already present in Eventually, virus-specific cells of the adaptive response to the body response arrive at the site of infection, targeting exposure ◦Non-specific infected cells and extracellular virus particles for ◦ Specific ◦Rapid Response ◦Slow response destruction or elimination ◦Limited and lower ◦High potency potency The diversity of viral populations enables some ◦Long term ◦no immunological particles to pass through the bottleneck, while others immunological memory are lost as the virus spreads memory Initiating an infection Three requirements must be met to ensure successful infection of an individual host: a sufficient number of infectious virus particles must be available to initiate infection; the cells at the site of infection must be physically accessible to the virus, susceptible (bear receptors for entry), and permissive (contain intracellular gene products needed for viral reproduction); and local antiviral defenses must be absent or, at least initially, quiescent The first requirement imposes a substantial barrier to any infection and represents a significant limitation In the transmission of virus from host to host In contrast, viruses that are spread by biting insects, contact with mucosal surfaces, or other means of direct contact, including contaminated needles, have little or no environmental exposure; the virus is transmitted directly for example, from mosquito to human Even after transmission from one host to another, infection may fail simply because the concentration of infectious virus particles is too low One can envision many paths to failure: the virus particle may adhere to a dead or dying cell, become attached to nonsusceptible cells by nonspecific protein-protein interactions, be swept away in the bloodstream, get stuck in mucus, or be degraded within a lysosome upon entry into a target cell The ratio of infectious to defective virus particles in a preparation can be calculated by dividing the number of infectious particles by the total number of particles in a sample Not every virus particle that binds to a susceptible and permissive cell can induce all the steps needed to produce progeny virus particles, and even those that can may be thwarted at any step of the viral reproductive cycle Successful infections must modulate or bypass host defenses Skin It [skin] serves obvious protective functions, but is also required for thermoregulation, control of hydration and evaporation, and integration of sensory information This outermost layer is a rather literal coat of armor against viral infection: many virus particles that land on intact skin are inactivated by dehydration, acids, or other inhibitors secreted by commensal microorganisms However, when the integrity of the dead cell layer is compromised by cuts, abrasions, or punctures, virus particles can access the rich array of live cells beneath the keratinized layer, including epithelial cells, endothelial cells, neuronal processes, and capillaries Superficial infections in the epidermis typically remain focalized, whereas deeper penetration of viruses in dermal or subdermal tissues can reach nearby blood vessels, lymphatics, and neurons, conduits that enable systemic transmission The body's response to a breach in the critical barrier formed by the skin is to make rapidly a hard, water-resistant shell over the wound, called a scab In addition, macrophages further aid the healing process by producing growth factors that promote cell proliferation. As the air dries the wound area, these formerly useful immune cells become part of the scab as well Respiratory tract Surfaces exposed to the environment but not covered by skin are lined by living cells and are at risk fore infection despite the continuous actions of self-cleansing mechanisms The tract is lined with a mucociliary blanket consisting of ciliates cells, mucus - secreting goblet cells, and subepithelial mucus-secreting glands Foreign particles deposited in the nasal cavity or upper respiratory tract are often trapped in mucus, carried to the back of the throat, swallowed, and destroyed in the low pH environment of the gut When coughing occurs, both the host and the virus benefit; the host expels virus-laden mucous with each productive cough, and the virus is carried out of the host, perhaps to infect another nearby Larger, virus-containing droplets are deposited in the nasal mucosa, whereas smaller droplets can penetrate deeper into the airways Or the alveoli Influenza neuraminidase cleared sialic acids that are abundant on the glycoproteins that form mucus; as a result, mucous membranes are degraded locally, affording access to the cells below Alimentary tract Virus particles that infect by the intestinal route must, at a minimum, be resistant to extremes of pH, proteases, and bile detergents The lumen of the alimentary tract, from mouth to anus, is "outside" of our bodies, and thus the anatomy of the alimentary tube possesses many features of the skin Like the skin, the gut has physical, chemical, and protein-based barriers that collectively limit viral survival and infection: the stomach is acidic, the intestine is alkaline, and proteases and bile salts are present at high concentrations While passage from the mouth to the stomach is generally considered a quick tip following a swallow, cells in the oropharynx appear to be permissive for human papillomaviruses, which can cause oropharyngeal squamous cell carcinoma Once in the stomach, a virus particle must endure stomach acid, which typically has a pH of 1.5 to 3.0, sufficiently low to denature most proteins of incoming food and many viruses Nearly the entire small intestinal surface is covered with columnar villas epithelial cells with apical surfaces that are densely packed with microvilli This brush border, together with a surface coat of glycoproteins and glycolipids and the overlying mucus layer, is permeable to electrolytes and nutrients but presents a barrier to microorganisms These small (~30-amino-acid) peptides [defensins] serve primarily to inactivate invasive or foreign bacteria by destabilizing the bacterial cell wall or by interfering with bacterial metabolism The M cell is very thin, resulting in a membrane-like bridge that separates the intestinal lumen from the subepithelial space While most viruses that can infect via the alimentary tract gain access via the mouth, it is possible for virus particles to enter the body through the lower gastrointestinal tract without passing through the upper tract Eyes Like the saliva, tears that are routinely produced to keep the eye hydrated also contain small quantities of antibodies and lysozymes Of Interest, the chemical composition of tears differs, depending on whether they are "basal" tears produced constantly in the healthy eye, "psychic tears" produced in response to emotion or stress, or " reflex tears" produced In response to noxious irritants, such as tear gas or onion vapor In most cases, viral reproduction is localized and results in inflammation of the conjunctiva, a condition called conjunctivitis or "pink eye" Injury to the eye that allows for viral entry need not to be a major trauma: small dust particles or rubbing one's eyes too aggressively may be sufficient to damage the protective layer and provide an opportunity for virus particles to access permissive cells Urogenital tract The vagina maintains a pH that is typically between 3.4 and 4.5; when the pH increases toward neutrality, many pathogens, including bacteria and yeast, can flourish Sexual activity can result in tears or abrasions In the vaginal epithelium or the urethra, allowing virus particles to enter. Some viruses infect the epithelium and produce local lesions Because herpesvirusEs cannot be cleared from infected hosts, recrudescence can occur following stress, natural changes in the thickness of the canal during the menstrual cycle, or other infections In pregnancy, infections by these viruses pose a particular risk to the developing fetus and can result in miscarriage, early delivery, or lifelong infection that begins in the neonate, dangers that can be mitigated by Caesarian delivery Human semen is a particularly robust carrier of viruses: it is estimated that up to 27 distinct viruses can reproduce in, and be spread by, semen Some of these viruses, including the papillomaviruses, may even cause mutations in the DNA of sperm, which could then fertilize an egg and pass along the virus-induced mutations to future generations Placenta Transplacental infections are distinct from perinatal infections, in which the virus is acquired via contact with maternal blood as the baby is delivered through the birth canal The placenta is the sole barrier and conduit between the maternal and fetal blood supply and is responsible for gas, waste, and nutrient exchange throughout pregnancy, and its morphology and constitution change throughout pregnancy Syncytiotrophoblasts lie at the maternal-fetal blood interface and are in direct contact with maternal blood; they are therefore crucial for protecting the fetus from circulating pathogens Some pathways that have been proposed to allow for viral vertical transmission include traversing the syncytiotrophoblast layer by antibody-dependent transcytosis, increased tropism for placental cell types that are more pervasive to virus infections, and maternal immune-mediated damage to the syncytiotrophoblast layer, thus allowing for breaches in the placental barrier Viral tropism First, in order for A urus to infect a cell, the cell must be susceptible; that is, it must have receptors that the virus binds to allow entry Successful production of viral progeny depends on cellular gene products (or other cellular components) to complete the infectious cycle, which may be synthesized by some cell types but not others Although a cell may be both susceptible and permissive, infection may not occur because virus particles are physically prevented from interacting with the tissue; thus, the host cells must be accessible to virus The cells in which a virus reproduces obviously influence the kind of disease that can occur, and thus tropism is a crucial parameter of pathogenesis In most hosts, a localized infection occurs at the site of infection, followed by latent infection of neurons that innervate that tissue Accessibility of viral receptors For example, if the cellular receptor is present only on the basal cell membrane of polarized epithelial cells, a virus that is only exposed to the apical cell surface cannot infect unless it reaches the basolateral surface by some means Non-susceptible (non-receptor-producing) cells can still be infected by alternative routes; for example, virus particles bound to antibodies can be taken up by Fc receptors Other host-virus interactions that regulate the infectious cycle Cellular proteases, present in some cells but not others, are often required to cleave viral proteins to form the mature infectious virus particle Vocab Tropism: the cellular and anatomical parameters that define the cells in which a virus can reproduce in vivo In mammals, the reproduction of influenza virus is restricted to epithelial cells of the upper and lower respiratory tracts, and its tropism is thought to be influenced by the production of the protease that processes HA0 Alteration of the hemagglutinin (HA) cleavage site so that it can be recognized by other cellular proteases dramatically changes the tropism of the virus and its pathogenicity; some highly virulent avian influenza virus strains contain an insertion of multiple basic amino acids at the cleavage site of HA0 A final emerging class of cellular macromolecules that can influence viral tropism are small, non-protein-encoding RNA species, called microRNAs Spread throughout the host Spread beyond the initial site of infection depends on multiple parameters, including the initial viral dose, the presence of viral receptors on other cells, and the relative rates of immune induction and release of infectious virus particles An infection that spreads beyond the primary site (usually near the point of viral entry) is said to be disseminated. If many organs are viral targets, the infection is described as systemic One important mechanism for avoiding local host defenses and facilitating spread within the body is the directional release of virus particles from polarized cells at a mucosal surface In such cases, local lateral spread from cell to cell may occur in the infected epithelium, but the underlying lymphatic and circulatory vessels are rarely infected The only areas in the brain or spinal cord that are targets for herpes simplex virus infection are those that contain neurons with axon terminals or dendrites connected to common sites of inoculation in the body Hematogenous spread Disseminated infections typically occur by transport through the bloodstream (hematogenous spread). Entry may occur through broken blood vessels, through direct inoculation, or by basolateral release of virus particles from infected capillary endothelial cells Hematogenous spread begins when newly synthesized particles produced at the entry site are released into extracellular fluids and are taken up by the local lymphatic vascular system Because the lymphatic system and circulatory system "meet" in lymph nodes, and because nodes are home to lymphocytes and monocytes, some viruses, such as human immunodeficiency virus type 1, replicate extensively in these cells Traversing the blood-brain barrier poses a particular challenge for a free vision, as the capillaries that make up this unique barrier limit the access of serum molecules to the brain Active viremia is a consequence of reproduction in the host, whereas passive viremia results when particles are introduced into the blood without viral reproduction at the site of entry Vocab The release of progeny virus particles into the blood after initial reproduction at the site of Viremia: describes the presence of infectious entry constitutes the primary viremia phase virus particles in the The delayed accumulation of a high concentration of infectious virus in the blood is termed blood secondary viremia The concentration of virus particles in blood is determined by the rate of their synthesis in permissive tissues and by how quickly they are released into, and removed from, the blood On average, individual virus particles may remain in the blood from 1 to 60 min, depending on parameters such as the physiology (e.g.,age and health) and the size and structural integrity of the virus particles Viremia is of diagnostic value to monitor the course of infection in an individual over time, and epidemiologists use the detection of viremia to identify infected individuals within a population Neural spread In some cases, neuronal spread is the definitive characteristic of pathogenesis, notably by rabies virus and alphaherpesviruses, which cause infections that primarily impact neuronal function or survival For those neurotic viruses that enter the brain via neuronal circuitry, viral reproduction usually occurs first in nonneuronal cells such as muscle cells near the site of infection Following reproduction in these cells, virus particles subsequently spread into efferent (e.g., sensory) or efferent (e.g., motor) nerve fibers that innervate the infected tissue, usually crossing neuromuscular junctions to do so Neurons are polarized cells with structurally and functionally distinct processes (axons and dendrites) that can be separated by enormous distances Rather, the neuronal cytoskeleton, including microtubules and actin, provides the "train tracks" that enable movement of mitochondria, synaptic vesicles, and virus particles to and from the synapse Virus spread by this mode can continue through chains of connected neurons of the peripheral nervous system and may eventually reach the spinal cord and brain, often with devastating results reactivation from the latent state results in viral reproduction in the primary neuron and subsequent transport of progeny virus particles from the neuron cell body back to the innervated peripheral tissues where the infection originated Organ invasion Once virus particles enter the blood or neurons and are dispersed from the primary site of infection, any subsequent reproduction requires invasion of other cells In some tissues, the endothelial cells are continuous with a dense basement membrane. at other sites, the endothelium contains gaps, and at still others, there may be sinusoids, in which macrophages form part of the blood-tissue junction Entry into organs with sinusoids Organs such as the liver, spleen, bone marrow, and adrenal glands are characterized by the presence of sinusoids, a type of capillary that has a large pore size to allow free exchange between the blood and the tissue However, the macrophages In organs that possess sinusoids often provide the portal for entry of viral particles into tissues Virus particles may be transcytosed across Kupffer and endothelial cells without reproduction to reach the underlying hepatocytes Entry into organs that lack sinusoids to enter tissues that lack sinusoids, and that have tighter or more continuous capillary endothelial cells, virus particles must first adhere to the endothelial cells before crossing into the tissue Invasion occurs because the endothelial cells that make up the capillaries of these tissues have pores or holes in the cell layer, called fenestrations, that permit virus particles Or virus infected cells to cross Organs with dense basement membranes In the central nervous system, connective tissue, and skeletal and cardiac muscle, Vocab capillary endothelial cells are supported by A dense basement membrane, which Diapedesis: some viruses raises an additional barrier to viral passage into the tissue traverse the endothelium In the central nervous system, the basement membrane, formed in part by hidden in infected astrocytic extensions (called "end-feet”) that align with the basolateral surface monocytes or of the capillary endothelium, is the foundation of the blood-brain barrier lymphocytes Some viruses pass through the capillary endothelium and enter the stroma of the choroid plexus, where they may then cross the epithelium into the cerebrospinal fluid either by transcytosis or by directed release following production of progeny virus particles Skin Destruction of cells by virus reproduction and the host immune system are the primary causes of most skin lesions Identifying a viral infection early has obvious containment benefits: by the time that the infection is recognized from the skin rash, viral transmission to other individuals may already have occurred Shedding of virus particles During localized infections in or near one of the body openings, shedding can occur from the primary site of virus reproduction Effective transmission of virus particles from one host to another depends on the concentration of released particles and the mechanisms by which the virus particles are introduced into the next host The shedding of small quantities of virions may be insufficient to cause new infections, while the shedding of high concentrations may facilitate transmission via minute quantities of tissue or body fluid An interesting feature of such infections is that the mosquito saliva also numbs the site, stops the blood from clotting, and induces inflammation, which can help to spread the infection Respiratory secretions Respiratory transmission depends on the density of virus particles in the secretion, and the duration of a liquid droplet in the air Such particles may not only come in contact with a naïve host but also penetrate into the lower respiratory tract. Nasal and oral secretions also frequently contaminate hands or tissues