Overview
The lecture builds one equation — virulent microbe + susceptible host = infection — and then unpacks both sides of it. It first defines the vocabulary (pathogen, pathogenicity, virulence, virulence factor) and the host side (what makes a person susceptible, and the layered defences a microbe has to overcome). It then shows that infection and the resulting pathology are both multifactorial: microbe, host and environment determine whether infection occurs, and damage comes from microbial factors and the host’s own inflammatory response together. Pseudomonas aeruginosa is the worked clinical example of an opportunistic, hospital-associated, multidrug-resistant pathogen, with Candida albicans and Influenza A virus showing that fungi and viruses use the same strategies. The lecture closes on virulence and resistance genes moving on mobile genetic elements, and on antimicrobial stewardship as the clinical response.
Core definitions and the central equation
- Pathogen — a microbe that can cause infection.
- Pathogenicity — the ability of a microbe to cause infection.
- Virulence — a measure of pathogenicity in a susceptible host.
- Virulence factor — a gene product that enables colonization of a susceptible host. Infection may result from expression of the factor or from the host response to it.
- The organising equation: virulent microbe + susceptible host = infection.
- Groups of pathogens that converge on disease:
- Bacteria — Gram+, Gram-, acid fast, anaerobes, chlamydiae, mycoplasmas, mycobacteria, rickettsiae, spirochaetes
- Fungi — yeasts, moulds
- Prions
- Parasites — protozoa, helminths
- Viruses — DNA (ss/ds), RNA (ss/ds)
The pathogen-classification diagram shows only group membership converging on "disease"; no further relationship between the groups is stated on the slide.
Host susceptibility
Definition: a person lacking immunity or resistance to a pathogen, and therefore at increased risk of infection.
Host factors that influence susceptibility and disease severity, with the examples given:
- Age — very young, very old
- Comorbidities — diabetes, cancer, HIV/AIDS, respiratory disease, heart disease
- Lifestyle — smoking, diet, obesity, exercise, alcohol intake
- Genetics — congenital immunodeficiency
- Immunization — non-vaccinated
- Medical interventions — dialysis, catheters, central lines, prostheses, surgery
- Medications — immunosuppressives, broad-spectrum antimicrobials
- Trauma — damage to barriers
- Socioeconomic — poor housing, over-crowding, poor nutrition, poor dentition, limited access to healthcare, poverty
The virulence-defence balance: three scenarios
Think of it as a see-saw between the microbe’s virulence factors and the host’s defences and physiological state (the host also supplies the nutrients and energy the microbe needs).
- Normal host — virulence balances host defences, so no infection; the beam sits level.
- Low virulence, weakened host — the host end is weighted down by impaired defences and physiology while the microbe is unchanged, and the balance tips to disease. These are opportunistic pathogens: often from the microbiome, causing infection when introduced into previously sterile sites, and requiring a susceptible host.
- High virulence, normal host — the microbe end is weighted down by strong virulence factors against normal defences, and the balance tips to disease. These are obligate pathogens: they carry specialized virulence factors and do not require a susceptible host.
The general rule: the more compromised the host, the fewer virulence traits the infecting microbe needs in order to cause infection.
Infection and pathology are both multifactorial
Infection depends on three interacting sets of factors (the epidemiological triangle of host, pathogen and environment, with disease at the centre):
- Microbial factors — the virulence of the microbe, through expression of multiple virulence factors.
- Host factors — susceptibility to infection, and the host response to the microbe.
- Environmental factors — transmission, route of entry, pH, temperature; transmission is common in healthcare settings.
Relevant bacterial cell structures named on the slide: cytoplasm, nucleoid, capsule, cell wall, cytoplasmic membrane, ribosomes, pili, flagella.
Pathology arises by two routes that converge on the same damaged host cell:
- Microbe-mediated pathogenesis — virulence factors (secreted toxins) directly damage host cells.
- Host-mediated pathogenesis — bacterial antigens and leukocytes drive a prolonged, delayed or inappropriate inflammatory/immune response that also damages somatic cells.
So pathology depends on both microbial virulence (toxins, enzymes, biofilms) and the host response (inflammation/immunity). There is a cycle of damage: virulence factors and inflammation cause cell death, which provokes further inflammation and further damage.
Host defences: layers of protection
Intrinsic (non-immune)
- Physical barriers — skin, mucous membranes
- Secretions — tears (lysozyme), sweat (NaCl)
- Physical removal — mucous and cilia
- pH — stomach, vagina
- Microbiome — competitive inhibition, antibacterial compounds
Immune — innate (non-specific)
- Phagocytosis
- Inflammation
- Pattern recognition systems
- Complement (alternative pathway)
- Cytokines, chemokines
Immune — adaptive (specific)
- Activated APC
- T cells (CD4, CD8)
- B cells (plasma cells, antibodies)
- Complement (classical pathway)
- Cytokines
Medical interventions, treatments and procedures can disrupt these defences, increasing host susceptibility to infection. Hospitalized patients often combine immunodeficiency, comorbidity and barrier-breaching interventions.
The microbiome as a source of infection
- The body is colonized by a complex community of microbes even in health, and this is an important source of infectious microbes in healthcare settings.
- Endogenous — the patient’s own organisms.
- Exogenous — organisms from others.
- Colonized sites are those exposed to the environment: skin, and mucous membranes (conjunctiva, oral cavity, URT, GIT, GUT).
- Other body sites are sterile or carry only transient organisms, which are removed by the immune response — but can cause disease in a susceptible host.
Normal microbiota by site, as listed on the slide:
| Site | Organisms |
|---|---|
| Conjunctiva | Coagulase-negative staphylococci; Haemophilus spp.; Staphylococcus aureus; Streptococcus spp. |
| Outer ear | Coagulase-negative staphylococci; diphtheroids; Pseudomonas; Enterobacteriaceae (occasionally) |
| Nose | Coagulase-negative staphylococci; viridans streptococci; S. aureus; Neisseria spp.; Haemophilus spp.; Streptococcus pneumoniae |
| Mouth and oropharynx | Viridans streptococci; coagulase-negative staphylococci; Veillonella spp.; Fusobacterium spp.; Treponema spp.; Porphyromonas and Prevotella spp.; Neisseria spp. and Branhamella catarrhalis; S. pneumoniae; beta-haemolytic streptococci (not group A); Candida spp.; Haemophilus spp.; diphtheroids; Actinomyces spp.; Eikenella corrodens; S. aureus |
| Stomach | Streptococcus; Staphylococcus; Lactobacillus; Peptostreptococcus |
| Skin | Coagulase-negative staphylococci; diphtheroids (incl. Propionibacterium acnes); S. aureus; Streptococcus spp.; Bacillus spp.; Malassezia furfur; Candida spp.; Mycobacterium spp. (occasionally) |
| Small intestine | Lactobacillus spp.; Bacteroides spp.; Clostridium spp.; Mycobacterium spp.; enterococci; Enterobacteriaceae |
| Large intestine | Bacteroides spp.; Fusobacterium spp.; Clostridium spp.; Peptostreptococcus spp.; Escherichia coli; Klebsiella spp.; Proteus spp.; Lactobacillus spp.; enterococci; Streptococcus spp.; Pseudomonas spp.; Acinetobacter spp.; coagulase-negative staphylococci; S. aureus; Mycobacterium spp.; Actinomyces spp. |
| Urethra | Coagulase-negative staphylococci; diphtheroids; Streptococcus spp.; Mycobacterium spp.; Bacteroides and Fusobacterium spp.; Peptostreptococcus spp. |
| Vagina | Lactobacillus spp.; Peptostreptococcus spp.; diphtheroids; Streptococcus spp.; Clostridium spp.; Bacteroides spp.; Candida spp.; Gardnerella vaginalis |
General strategies of bacterial virulence
Disease usually requires expression of multiple virulence factors, working in sequence:
- Attachment to host cells — via pili, fimbriae, capsules and surface molecules such as LPS.
- Resisting host defences and multiplying — anti-phagocytic capsules, inhibition of leukocyte activity, degradation of immunoglobulins, and motility.
- Persisting in biofilms — bacteria embedded in a sticky matrix, more resistant to removal by host immunity and by antimicrobials. 50-80% of infections are associated with biofilms.
- Damaging host tissue — through exotoxins, enzymes and/or host cell invasion. The immune and inflammatory response against the pathogen also causes damage; both contribute to pathology.
Beyond bacteria: fungi and parasites also attach, resist host defences and multiply in order to cause disease. In viral infections, damage is due to replication of the virus in the host cell, or to immune responses directed at virally infected cells. Antigenic variation means previous immune memory functions less well, because a new set of epitopes is presented to the host (e.g. influenza A virus).
Pseudomonas aeruginosa
Organism and epidemiology
- Gram-negative rod.
- 3-5% of people colonised, as part of the microbiome (skin, gut).
- 20% of hospital inpatients colonised — a cause of hospital-acquired infection (HAI) with significant mortality.
- Also environmental: soil and water.
Clinical disease
- LRTI (notably in cystic fibrosis)
- Sepsis
- Bone and joint infections
- UTI
- Ear and eye infections
- Wound infections, including burns
- Folliculitis
Recognisable clinical features shown: Gram-negative pink rods on Gram stain; polar flagella on EM; corneal ulcer with conjunctival injection; wound exudate stained green; pustular papular folliculitis rash; purulent discharge from the external ear canal.
Pathogenesis — an opportunistic pathogen requiring a susceptible host
- Disruption of physical barriers — burns, IV lines, catheters, ET tubes.
- Immune dysfunction — neonates, HIV/AIDS, neutropenia, immunosuppressive drugs, ICU, transplants.
- Broad-spectrum antimicrobials — disrupt the normal microbiome.
Virulence factors
- Biofilms and capsules — alginate/polysaccharide EPS; give immune evasion from phagocytes, complement and antibodies; and antimicrobial resistance.
- Motility — flagella (a PAMP sensed via TLR5); chemotaxis towards sugars in respiratory mucous, relevant in CF.
- Adhesins — LPS, pili, fimbriae, capsule.
- Invasins — enzymes that break down barriers: haemolysins, elastases, collagenases.
- Factors affecting the host response — leukocidins, proteases, catalase.
- Toxins
- LPS — a PAMP acting via TLR4, causing inflammation.
- Exotoxin A — stops protein synthesis (acts on host EF2), causing cell death.
- Pyocyanin — induces inflammation and paralyses cilia; the green pigment seen in wound exudate.
Additional factors labelled on the schematic: quorum-sensing signals HSL and PQS; secreted alkaline protease and elastase acting on the epithelium and tight junctions; phospholipase; pyoverdine associated with iron acquisition; pyocyanin acting on ROS/glutathione/NADPH in the host cell; and a type III secretion system (T3SS) needle injecting the effectors ExoU, ExoS, ExoT and ExoY directly into the host cell.
Why it is difficult to treat
- Multidrug resistant, related to exposure to soil organisms.
- Multiple resistance mechanisms — efflux pumps, porins, β-lactamases.
- Rapidly acquires resistance — by mutation and by gene transfer via R plasmids.
- Biofilms.
- Comorbidities in the affected patients.
Treatment
- Combinations:
- Anti-pseudomonal penicillin + aminoglycoside
- Anti-pseudomonal penicillin + β-lactamase inhibitor (example given: piperacillin + tazobactam)
- OR broad-spectrum drugs: carbapenems, colistin.
Antimicrobial resistance complicates treatment of P. aeruginosa: therapy is problematic and requires combinations of antimicrobials or broad-spectrum antimicrobials.
Virulence beyond bacteria: Candida albicans
- 50-80% of people colonised — oral cavity, GIT, UGT.
- Commensal as the yeast form; infection as the mould form (budding oval yeast cells versus branching hyphae/pseudohyphae).
- In healthy hosts: mucocutaneous infections (e.g. white/creamy mucosal plaques).
- In immunocompromised hosts: systemic, invasive infections with high mortality.
- A cause of HAI, particularly in ICU and immunocompromised patients.
- Virulence strategies: attachment, biofilms, immune evasion, enzymes.
- Antifungal resistance is an emerging challenge.
Virulence beyond bacteria: Influenza A
Two major surface antigens on the viral lipid membrane:
- HA (haemagglutinin) — attachment and uptake.
- NA (neuraminidase) — release and transmission.
Antigenic variation:
| Antigenic drift | Antigenic shift | |
|---|---|---|
| Mechanism | RNA virus undergoing constant mutation; small changes to the existing surface antigens | Coinfection of an animal, with repackaging of viral RNA; surface antigens replaced by a different type |
| Immunity | Some protective antibody remains | New virus, no pre-existing immunity |
| Consequence | Less serious infections; seasonal epidemics | More serious infections; pandemics |
Virulence is always evolving
- Virulence genes may sit on mobile genetic elements (MGE): plasmids, transposons, phages.
- Bacteria readily take up MGE by three routes:
- Transformation — uptake of free DNA released from a dead bacterium by a competent recipient.
- Transduction — transfer via a bacteriophage that injects the gene into a recipient.
- Conjugation — transfer of a plasmid from donor to recipient by direct contact via a pilus.
- Antimicrobial resistance: use of antimicrobials exerts selection pressure, and any use promotes resistance (overuse and inappropriate use especially).
Appropriate use and prescription of antimicrobials is a challenge for future clinical practice — antimicrobial stewardship is crucial for the future of currently available antimicrobials.
Summary of the lecture’s own take-home points
- Virulence is a measure of pathogenicity, or ability to cause disease.
- Virulence factors are gene products produced by microbes to colonize the host: adhesins, toxins, enzymes, immune evasion, biofilms, capsules.
- Infection arises when these factors are expressed in a susceptible host. Host susceptibility matters, susceptible hosts are common in healthcare settings, the host response determines severity, and pathology depends on both microbe and host factors.
- Fungi and viruses (and parasites) use similar strategies to cause disease.
- Virulence factors are encoded on MGE and readily transmissible; antimicrobial resistance is a major concern, and appropriate prescription controls its spread.
Transcript flags carried over: the pathogen-classification diagram on slide 5 states only group membership converging on "disease"; the four clinical/laboratory photographs on the transition slide are uncaptioned, so the specific organisms and diagnoses shown are not stated. The final four pages of the PDF are duplicate 6-up handout thumbnails of earlier slides and contain no new content.
Self-test
- Define pathogenicity and virulence, and state how they differ.
- Define a virulence factor, and state the two ways infection may result from one.
- List the five groups of pathogens shown as converging on disease, with the subdivisions given for bacteria.
- Define host susceptibility.
- List the nine categories of host factor that influence susceptibility and disease severity, with one example of each.
- Distinguish an opportunistic pathogen from an obligate pathogen in terms of virulence and the host required.
- Explain the general rule relating the degree of host compromise to the number of virulence traits a microbe needs.
- List the three sets of factors that make infection multifactorial, with the components given for each.
- Distinguish microbe-mediated from host-mediated pathogenesis, and state what the two have in common.
- Explain the cycle of damage in infection.
- List the five intrinsic (non-immune) layers of host defence, with an example of each.
- List the components of innate and of adaptive immunity given as host defences, and state which complement pathway belongs to each.
- Explain why hospitalized patients are disproportionately susceptible to infection.
- Distinguish endogenous from exogenous sources of infectious microbes in a healthcare setting, and name the body sites that are normally colonized.
- Describe the four sequential strategies bacteria use to cause disease, naming the factors involved at each step.
- Define a biofilm and state what proportion of infections are associated with one and why biofilms matter clinically.
- Explain how antigenic variation undermines pre-existing immunity.
- Describe how damage arises in viral infection.
- State the colonisation rates of P. aeruginosa in the general population and in hospital inpatients, and its environmental reservoirs.
- List the clinical diseases caused by P. aeruginosa.
- List the three routes by which a host becomes susceptible to P. aeruginosa, with examples of each.
- List the six categories of P. aeruginosa virulence factor, naming at least one factor in each.
- Explain the mechanism and effect of each of the three P. aeruginosa toxins named.
- Explain why P. aeruginosa infections are difficult to treat, listing its resistance mechanisms and the ways it acquires resistance.
- State the antimicrobial regimens recommended for P. aeruginosa.
- Distinguish the commensal from the pathogenic form of Candida albicans, and describe how the disease it causes differs between healthy and immunocompromised hosts.
- Distinguish the functions of haemagglutinin and neuraminidase in influenza A.
- Distinguish antigenic drift from antigenic shift by mechanism, residual immunity and epidemiological consequence.
- List the mobile genetic elements that can carry virulence genes, and describe the three mechanisms by which bacteria take them up.
- Explain why any use of antimicrobials promotes resistance, and state the clinical response to this.
- A patient in ICU has a burn wound managed with an IV line and a course of broad-spectrum antimicrobials. The dressing shows green exudate. Explain which organism this suggests, which host defences have been breached, and which virulence factor produces the green colour.
- A patient with cystic fibrosis develops a chronic lower respiratory tract infection that persists despite antimicrobial therapy. Explain, using virulence factors from the lecture, why the organism reaches and then persists in the airway.
- Two patients are infected by the same organism; one has mild disease and one develops severe tissue destruction. Using the lecture’s model of pathology, explain how this can occur even with an identical microbe.
- Integrative: explain how the equation “virulent microbe + susceptible host = infection” accounts for both an opportunistic hospital-acquired P. aeruginosa infection and an influenza pandemic.
Answers
Reveal answers
- Pathogenicity is the ability of a microbe to cause infection; virulence is a measure of that pathogenicity in a susceptible host. Pathogenicity is the capacity, virulence is its magnitude measured against a host.
- A gene product that enables colonization of a susceptible host. Infection may result either from expression of the factor itself or from the host’s response to it.
- Bacteria (Gram+, Gram-, acid fast, anaerobes, chlamydiae, mycoplasmas, mycobacteria, rickettsiae, spirochaetes); fungi (yeasts, moulds); prions; parasites (protozoa, helminths); viruses (DNA ss/ds, RNA ss/ds).
- A person lacking immunity or resistance to a pathogen, and therefore at increased risk of infection.
- Age (very young/very old); comorbidities (diabetes, cancer, HIV/AIDS, respiratory or heart disease); lifestyle (smoking, diet, obesity, exercise, alcohol); genetics (congenital immunodeficiency); immunization (non-vaccinated); medical interventions (dialysis, catheters, central lines, prostheses, surgery); medications (immunosuppressives, broad-spectrum antimicrobials); trauma (damage to barriers); socioeconomic (poor housing, overcrowding, poor nutrition, poor dentition, limited healthcare access, poverty).
- Opportunistic pathogens have low virulence, are often derived from the microbiome, cause infection when introduced into previously sterile sites, and require a susceptible host. Obligate pathogens have high virulence with specialized virulence factors and do not require a susceptible host.
- The more compromised the host, the fewer virulence traits the infecting microbe needs in order to cause infection — it is a balance, so weakening one side lowers the requirement on the other.
- Microbial factors — virulence of the microbe, through expression of multiple virulence factors. Host factors — susceptibility to infection and the host response to the microbe. Environmental factors — transmission, route of entry, pH, temperature, with transmission common in healthcare settings.
- Microbe-mediated pathogenesis is direct damage to host cells by virulence factors such as secreted toxins. Host-mediated pathogenesis is damage from a prolonged, delayed or inappropriate inflammatory/immune response to bacterial antigens and leukocyte activity. Both converge on the same outcome, somatic cell damage, and both contribute to pathology.
- Virulence factors and inflammation cause cell death; that damage provokes further inflammation and further damage, which perpetuates the cycle.
- Physical barriers (skin, mucous membranes); secretions (tears containing lysozyme, sweat containing NaCl); physical removal (mucous and cilia); pH (stomach, vagina); microbiome (competitive inhibition and antibacterial compounds).
- Innate (non-specific): phagocytosis, inflammation, pattern recognition systems, complement by the alternative pathway, cytokines and chemokines. Adaptive (specific): activated APC, T cells (CD4, CD8), B cells (plasma cells and antibodies), complement by the classical pathway, cytokines.
- They often combine immunodeficiency, comorbidities and interventions or treatments that increase risk; medical procedures, interventions and treatments disrupt the intrinsic and immune barriers, and transmission is common in healthcare settings.
- Endogenous means the patient’s own organisms; exogenous means organisms acquired from others. Normally colonized sites are those exposed to the environment: skin and the mucous membranes of the conjunctiva, oral cavity, upper respiratory tract, GIT and GUT. Other sites are sterile or carry transient organisms only.
- (1) Attachment to host cells via pili, fimbriae, capsules and surface molecules such as LPS. (2) Resisting host defences and multiplying, using anti-phagocytic capsules, inhibition of leukocyte activity, degradation of immunoglobulins and motility. (3) Forming biofilms that resist immunity and antimicrobials. (4) Damaging host tissue through exotoxins, enzymes and/or host cell invasion, with additional damage from the immune and inflammatory response.
- A biofilm is bacteria embedded in a sticky matrix. 50-80% of infections are associated with biofilms. They matter because bacteria within them are more resistant to removal by host immunity and to antimicrobials.
- Antigenic variation presents a new set of epitopes to the host, so previously formed immune memory functions less well against the altered organism — e.g. influenza A virus.
- Damage results either from replication of the virus in the host cell, or from immune responses directed at virally infected cells.
- 3-5% of people are colonised as part of the microbiome (skin, gut); 20% of hospital inpatients are colonised. Environmental reservoirs are soil and water.
- Lower respiratory tract infection (notably in cystic fibrosis), sepsis, bone and joint infections, UTI, ear and eye infections, wound infections including burns, and folliculitis.
- Disruption of physical barriers (burns, IV lines, catheters, ET tubes); immune dysfunction (neonates, HIV/AIDS, neutropenia, immunosuppressive drugs, ICU, transplants); broad-spectrum antimicrobials that disrupt the normal microbiome.
- Biofilms and capsules (alginate/polysaccharide EPS); motility (flagella, chemotaxis); adhesins (LPS, pili, fimbriae, capsule); invasins (haemolysins, elastases, collagenases); factors affecting the host response (leukocidins, proteases, catalase); toxins (LPS, exotoxin A, pyocyanin).
- LPS acts as a PAMP via TLR4 to induce inflammation. Exotoxin A stops protein synthesis by acting on host EF2, causing cell death. Pyocyanin induces inflammation and paralyses cilia, and is the green pigment seen clinically.
- It is multidrug resistant, associated with exposure to soil organisms, and carries multiple resistance mechanisms — efflux pumps, porins and β-lactamases. It rapidly acquires further resistance by mutation and by gene transfer on R plasmids. Biofilms protect it from antimicrobials, and affected patients have comorbidities.
- Combination therapy — an anti-pseudomonal penicillin plus an aminoglycoside, or an anti-pseudomonal penicillin plus a β-lactamase inhibitor (e.g. piperacillin + tazobactam) — or broad-spectrum drugs such as carbapenems or colistin.
- The commensal form is the yeast; infection is associated with the mould (hyphal) form. 50-80% of people are colonised (oral, GIT, UGT). Healthy hosts get mucocutaneous infections; immunocompromised hosts get systemic, invasive infections with high mortality.
- Haemagglutinin (HA) mediates attachment and uptake; neuraminidase (NA) mediates release and transmission.
- Drift: constant mutation of the RNA virus produces small changes in the existing surface antigens; some protective antibody remains, infections are less serious, and it causes seasonal epidemics. Shift: coinfection of an animal allows repackaging of viral RNA, producing a virus with new surface antigens; there is no pre-existing immunity, infections are more serious, and it causes pandemics.
- Plasmids, transposons and phages. Transformation — uptake of free DNA released by a dead bacterium. Transduction — transfer via a bacteriophage that injects the gene into the recipient. Conjugation — plasmid transfer from donor to recipient by direct contact via a pilus.
- Antimicrobial use exerts selection pressure favouring resistant organisms, so any use promotes resistance, with overuse and inappropriate use worst. The response is appropriate use and prescription — antimicrobial stewardship.
- Pseudomonas aeruginosa. The breached defences are the physical barriers (burn and IV line) plus the microbiome, disrupted by the broad-spectrum antimicrobials; ICU status adds immune dysfunction. The green colour is produced by pyocyanin.
- Flagella provide motility with chemotaxis towards the sugars in respiratory mucous, bringing the organism to the CF airway; adhesins (LPS, pili, fimbriae, capsule) attach it. It then forms an alginate/polysaccharide biofilm and capsule, which gives immune evasion from phagocytes, complement and antibodies, and resistance to antimicrobials, so the infection persists despite therapy.
- Pathology depends on both microbial virulence and the host response. Even with identical microbial factors, a prolonged, delayed or inappropriate inflammatory/immune response in one host produces additional somatic cell damage and feeds the cycle of damage, so the host response determines severity of disease.
- The equation is a balance. In hospital-acquired P. aeruginosa infection the microbe side is low-virulence and opportunistic, but the host side is heavily weighted by breached barriers, immune dysfunction and disrupted microbiome, so the balance tips to infection. In an influenza pandemic the host side is normal but the microbe side is weighted by antigenic shift, which produces new surface antigens against which no host has immunity, so the balance tips to infection in otherwise non-susceptible people. Either side alone is insufficient; infection requires the sum.