Review Roles of Microorganisms as Parasites and Pathogens That Cause Infection and Disease
Infect Immun. 2000 Dec; 68(12): 6511–6518.
Host-Pathogen Interactions: Basic Concepts of Microbial Commensalism, Colonization, Infection, and Disease
Editor: D. A. Portnoy
Most of the terminology used to define the host-microbe interaction has been in apply for nearly a century. Early on in this menstruum, microbes were thought to be primary aggressors that governed the host-pathogen interaction, resulting in affliction. Later, new information about the attributes of microbes and their hosts resulted in the understanding that the host-pathogen interaction does non always result in disease. This recognition, in turn, led to the introduction of terms to explain states in which microbes exist within hosts without causing overt illness and why some microbes only cause disease in certain hosts. Commensal, carrier country, and opportunist were terms put forth to account for microbes and conditions that were sometimes associated with disease but for which Koch's postulates could non be fulfilled for one reason or another. Well-nigh of these terms were originally proposed to describe the behavior of particular microbes, rather than to ascertain a more than full general host-microbe relationship.
Recently, nosotros reviewed the concepts of virulence and pathogenicity and described how the definitions for these terms changed over the years as microbiologists tried to notice ways to convey that microbial pathogenesis reflects an interaction betwixt two entities, host and pathogen (vii). Based on the concept that host damage was the nigh relevant outcome of the host-pathogen interaction, we proposed revisions to the definitions of the terms pathogen, pathogenicity, and virulence (7). However, the proposed framework suggested a need to reexamine the terms used to ascertain the outcomes of host-microbe interactions. Here, we critically review the origin and historical evolution of fundamental concepts used to describe the upshot of host-microbe interactions, namely, infection, commensalism, colonization, persistence, infection, and illness. We propose that the meaning of these terms can be antiseptic by placing them in the context of the impairment framework put forth previously (7).
Lexicon OF MICROBIAL PATHOGENESIS
Once the germ theory of disease was accustomed, microbes were considered to be pathogens if they met the stipulations of Koch'south postulate. Nevertheless, it rapidly became apparent that (i) although at that place are many microbes, most human being infections were caused past only a few; (ii) some microbes were classified as pathogens although they did not cause disease in every host; and (iii) some microbes were classified as nonpathogens, although they did crusade disease in certain hosts (for an early review, see reference 56). In improver, information technology became evident that normal individuals harbored, in their mouth, gut, and skin, large numbers of microbes that did not cause disease. New ideas and terminology, heretofore referred to collectively every bit a dictionary, were devised to accommodate this data.
By the early twentieth century, it was apparent that pathogenicity was neither an invariant nor a stable characteristic of about microbes and that the acquisition of pathogenic microbes was not necessarily synonymous with disease. In the laboratory, the successful attenuation of pathogens revealed that virulence could be increased or decreased by animal passage and/or in vitro civilisation (for a review of early experimentation, meet reference 4). This scientific advance somewhen led to the evolution of vaccines that controlled many of the major childhood diseases of the past. In the clinical realm, it was recognized that a microbe responsible for an epidemic illness could exist isolated from both symptomatic and asymptomatic individuals in the midst of an epidemic. For case, Henrici noted that only a small number of individuals developed disease when epidemics of cerebrospinal meningitis (Neisseria meningiditis) occurred in a community, whereas others carried the leaner but remained salubrious (i.due east., carriers); nonetheless, the bulk were neither sick nor carriers (18). Based on the ability to civilisation staphylococci and streptococci from nearly people despite the absenteeism of any manifestation of illness, Kolmer proposed a status chosen subinfection (26). This concept blurred the distinction between pathogens and nonpathogens and challenged a prevailing concept of microbial pathogenesis that was based on Koch's postulate. The recognition of the carrier state was problematic vis a vis the terminology of the time, because a necessary condition for associating certain pathogens with particular diseases was that the converse of Koch's postulate should be fulfilled; the causative microbe should not exist institute in unaffected individuals (55). Yet, the carrier state had not been accounted for in the formulation of Koch's postulate, and the recovery of pathogens from good for you hosts challenged the second part of the postulate that a parasite "occurs in no other disease equally a fortuitous and nonpathogenic parasite" (postulate wording as suggested by Evans [12]).
The description of the carrier state dislocated existing definitions of pathogens. To both explain the carrier state and preserve the distinction betwixt pathogenic and nonpathogenic microbes, the concept that host and pathogen could adapt to one another was put along. Karsner and Ecker described this adaptation as involving changes to both host and microbe, such that the host suffered no impairment and the microbe was resistant to the immune system (25). Similarly, Park and Williams described the carrier state as a commensal development by the pathogenic microorganism (36). Later, the view emerged that the carrier state was transient and true pathogens elicited immune responses that eliminated the pathogens, whereas commensals did not (54). Asymptomatic carriage of pathogens that elicited immunity was considered to exist a benefit to the host that was tolerated at the hazard of serious illness (54). Conversely, the recognition that a carrier land could follow resolution of clinical disease, e.g., for Salmonella enterica serovar Typhi, illustrated that in certain hosts in that location was a persistent risk of manual, and possibly reacquisition, of infection. Another variation of the carrier state with great clinical importance is "microbial persistence," which refers to the situation in which susceptible pathogens are not eradicated despite antimicrobial therapy (31). The carrier state remains poorly understood, and, as noted by Smith, this surface area of study is relatively underrepresented in microbial pathogenesis research (41). Although the concept of the carrier state may have undermined the pathogen-centered view of microbial pathogenesis, it invoked a mutability that paved the manner for defining host-microbe interaction equally a regulated human relationship.
Intrinsic to the terms commensalism, colonization, and the carrier state was the concept that some microbes had the chapters to persist in their hosts. According to a model proposed by Blaser (iii), ongoing interactions between host and microbe accept different outcomes that depend upon regulation of the host-microbe relationship and coevolution of host and microbe favors an outcome in which the cost of eliminating the microbe is high. In the late twentieth century, studies of bacterial pathogenesis led to the identification of molecular differences between pathogenic and nonpathogenic microbes, and this engendered the belief that pathogens and nonpathogens were intrinsically different (14, 15, 17, 41). In this regard, historical definitions of terms used in the field of microbial pathogenesis accept focused on distinctions betwixt pathogens and nonpathogens rather than on the frequently divergent outcomes that frequently characterize different host-microbe relationships. The existence of the latter underscores the demand for terminology that describes host-microbe interaction, rather than pathogen-specific characteristics.
Tabular array 1 lists historical definitions for terms commonly used in the field of microbial pathogenesis. These definitions reveal a conceptual evolution that paralleled emerging concepts in microbial pathogenesis and clinical infectious diseases, albeit in some disharmonize with current concepts of infection and immunity. For example, the implication that states of colonization or commensalism do not invoke an immune response are inconsistent with bear witness that normal microflora can elicit specific antibody responses (reviewed in reference 46). In fact, antibodies to Staphylococcus aureus and Candida albicans are frequent in healthy individuals that harbor these microbes without illness (16, 38, 39), and carriers of group A Streptococcus often accept titers of antibody to streptococcal antigens which are attributed to prior infection (47). Moreover, the presence of antibodies can represent outcomes equally diverse every bit ongoing viral replication (e.yard., in homo immunodeficiency virus [HIV] natural or vaccine-elicited immunity, latency, carriage, and cross-reactivity with antigens of some other microbe or an unknown antigen. However, if the presence of antibodies implies nowadays or past infection, the view that certain states (e.g., colonization and the carrier state) are precursors to infection requires modification. Thus, rather than providing definitions based on the outcome of host-microbe interaction, the current lexicon puts forth terms that are primarily intended to define a pathogen and whether or not it causes infection and/or disease.
TABLE 1
Some historical definitions in the field of microbial pathogenesisa
| Term | Definitionb | Reference |
|---|---|---|
| Carrier land | The retained invader (eastward.g., microbe)—under the influence of the allowed surround—gradually dissociates into a saprophytic land | 57 |
| A country of beast adaptation whereby the microbe and its products cause no damage; in this state the "organisms themselves have probably developed a state of resistance against substances which ordinarily would destroy the organisms and neutralize their products" | 25 | |
| When an organism of relatively high pathogenicity may appear in the normal flora without causing disease | 44 | |
| Certain individuals may continue to harbor a pathogen after clinical recovery from an infectious disease and may serve as carriers of infection | 35 | |
| Colonization | An agent is considered to colonize a host when its presence in that host does not cause a specific immune response or infection | 34 |
| Microorganisms which do not belong to the normal flora of the host but practice not inflict local damage to the host | 51 | |
| The advent or increment in numbers of a particular invasive bacterial species in the resident microflora | 52 | |
| Implantation of a microbe at a site, such as multiplication of staphylococci in the anterior nares | 24 | |
| Multiplication of an organism on a body surface without evoking an immune response | 13 | |
| Commensal | A harmless parasite | 36 |
| The organisms of the normal flora | 44 | |
| Microbes that tin can found themselves in the pharynx, nose, or intestines without impairment to the host | 53 | |
| Nonpathogenic organisms nowadays in varying numbers at sites of the normal host'due south body that are in contact with the surround | 1 | |
| An organism which "eats at the same table" every bit some other of a different species but which confers on the latter neither benefit nor harm | 35 | |
| Pertaining to or characterized by commensalism; an organism participating in commensalism | 28 | |
| Commensalism | The mutual but almost inconsequential association between bacteria and higher organisms | 57 |
| The presence of microorganisms on skin and mucous membranes | 33 | |
| A symbiotic association between host and microorganism in which the microorganism is benefitted but the host is neither helped nor harmed | 32 | |
| An organism that lives in close association with another of a different species without either harming or benefitting it | 23 | |
| A class of parasitism in which no injury is dealt to either participant by the other | 19 | |
| The ability (of a microorganism) to live on the external or internal surfaces of the body without causing affliction | 48 | |
| A symbiotic relationship in which one species derives do good and the other is unharmed | 28 | |
| Germ carrier or carrier | A person who harbors and releases pathogenic organisms without manifesting symptoms of the disease associated with the pathogen | 24 |
| A host that harbors a pathogenic organism in a commensal country | 36 | |
| Good for you individuals who harbor in their trunk parasitic organisms which are harmful to others | 18 | |
| Referred to as subinfection, the country whereby a microbe is intimately associated with and has its normal habitat in a certain part of the body and does no harm until special weather condition arise, when it may rapidly invade the tissues and produce infection | 26 | |
| A carrier is a person, animate being, or arthropod who harbors a specific infectious amanuensis in the absence of clinical illness with or without a detectable immune response | thirteen | |
| Infection | The invasion of the body tissues by microorganisms resulting in disease | 18 |
| When microparasites have passed the normal barriers of the skin or mucous membranes and have invaded and proliferated in the deeper tissues | 26 | |
| A process in which an organism enters, establishes itself, and multiplies in the host (non in others) | 32 | |
| Invasion of the body by harmful organisms (pathogens), such equally bacteria, fungi, protozoa, rickettsiae, or viruses | 23 | |
| The process whereby pathogenic organisms become established and multiply in or on the torso of the host | 24 | |
| The degradation, colonization, and multiplication of a microorganism in a host; normally accompanied by a host response | 13 | |
| Invasion of the body with organisms that have the potential to cause disease | 28 | |
| Infestation | Distinct from infection in that it applies specifically to animal parasites of macroscopic size, such every bit intestinal worms | 26 |
| Infectious affliction | The upshot of parasitism in which no mutual adaptation has taken place and in which the invasion of the host by the parasite is marked past a struggle, the local and systemic manifestations of which found the disease | 56 |
| The abnormal state resulting from the deleterious local and general interaction between a host and an invading parasite, with consequent tissue changes and symptoms | 26 | |
| The manifestations of the fight between the affliction-producing or pathogenic organisms and the host with all its defence mechanisms | 33 | |
| Infection that becomes apparent | 32 | |
| Mutualism | A relation between two different organisms in which both are benefitted | 32 |
| Commensalism in which the human relationship is mutually beneficial | nineteen | |
| Opportunist or opportunistic | Microbes which cause no overt clinical or pathological weather condition in the normal state merely can become invasive when the defenses are disturbed | 37 |
| Pathogens which attack persons with compromised immune function | 35 | |
| These infections represent the colonization of ordinarily sterile tissues by bacteria from tissues that always support autochthonous populations, and considering these autochthonous organisms are well adapted for survival on other tissue surfaces of the same animal, their command and clearance poses a whole spectrum of unique problems | viii | |
| Pathogen not able to cause affliction in salubrious hosts but simply in those with impaired defense mechanisms | 1 | |
| Normally harmless organisms which take the opportunity afforded by lowered host resistance to human action every bit pathogens | 48 |
In summary, practically all past treatises on the field of study of host-microbe interaction made some distinction between colonization, infection, and disease. Nevertheless, the footing for the definitions of these terms was embedded in examples of specific microbes rather than in a general framework. The lack of such a framework has led to some ambiguity in the meaning of these terms.
IMPACT OF Irresolute SPECTRUM OF INFECTIOUS DISEASES ON Lexicon
Though many historical definitions (Tabular array i) are adequate when considered in the context of specific microbes and diseases, most definitions practise non account for the varied outcomes of the host-microbe interaction. Early on definitions were formulated post-obit the rapid acquisition of new cognition in the late nineteenth century. At that time, the distinction between pathogenic, nonpathogenic, and commensal organisms may have been more clear-cutting, since the majority of human hosts probably had what would be considered normal immunity today, as those with immune harm were unlikely to survive babyhood. The adjective classical has been applied to pathogens that were major causes of infectious disease in the past (54). Nevertheless, the introduction of sanitation, serum therapy, vaccination, and then effective antimicrobial therapy reduced the prevalence of and mortality from classical pathogens, though such microbes remain a major health trouble in underdeveloped regions. Past the 1950s, neoplasia and inflammatory and degenerative diseases, rather than infectious diseases, were thought to be the major medical problems in industrialized nations. However, the development of corticosteroid and cytotoxic therapies, organ transplantation, invasive surgeries, and ultimately the catastrophe of the HIV epidemic, produced a new population of human being hosts with impaired immune systems (27, 51) that were vulnerable to infections with diverse microbes previously idea to be nonpathogenic (2).
A major change in the prevalence of sure pathogens occurred in the twentieth century. This was exemplified past the shift in the etiologic agents of bloodstream infections from gram-positive to gram-negative microbes in the early office of the century, and and then back once more to gram-positive and fungal microbes toward the finish of the century (11, fourteen). The primary cause of these shifts was antibody option. Since multiple microbes may be present in the hospitalized setting, infection represents an outcome of selective pressures in the context of the host-microbe relationship. Unexpected outcomes of the host-microbe relationship are all-time illustrated by the increased prevalence of unusual infections in individuals with advanced HIV infection. For example, by the middle of the first decade of the HIV epidemic in the early 1990s, Cryptococcus neoformans was the nearly frequent cause of meningitis in New York Urban center, when the more 1,000 cases of cryptococcal meningitis (9) outnumbered the 285 cases of meningitis caused by all bacterial pathogens (29). This reflects the influence of the HIV epidemic upon the spectrum of infectious diseases in a population likewise as the impact of the introduction of an effective vaccine against an important pathogen, namely, Haemophilus influenzae blazon b.
The recognition that microbes thought to be nonpathogens caused disease in certain hosts challenged the definitions of saprophyte and commensal. As a event, boosted terms were added to the lexicon in an endeavor to discover terminology that could suit the new medical and scientific findings (Table 1). In addition to the terms listed in Table one, other terms and adjectives used to depict microbes and their interactions with the host in the literature include pure saprophytes (57), pure parasite (57), half parasite (57), classical (54), persister (31), nosocomial (1), iatrogenic (ane), convalescent carrier (48), precocious carrier (48), chronic carrier (48), contact carrier (48), symptomless carrier (48), and emerging and reemerging (43). For instance, an opportunistic microorganism has been defined as "one that utilizes the opportunity offered past weakened defence mechanisms to inflict harm to the host" simply does not exclude pathogenicity for a normal host when a big inoculum or specific virulence factors can overcome normal defenses (51). This definition was so broad that, depending on the clinical situation, it could also include Streptococcus pneumoniae, S. aureus, and Streptococcus pyogenes, which besides cause illness in normal individuals (51). In this regard, it has been noted that if invasion and disease crave a breakdown in normal defenses, then all infectious agents can really be considered opportunistic (27). These definitions illustrate that although the concept of opportunism has been extremely important for our understanding of the host-microbe human relationship in the setting of immune impairment, the term opportunistic does not convey a universal meaning and its utilize should probably be abandoned.
INADEQUACY OF Lexicon IN CLINICAL PRACTICE
Microbes capable of causing illness are routinely cultured from patients, and the decision to administrate antimicrobial therapy often depends on whether the microbe is judged to exist a pathogen or colonizer. The medical literature contains different conclusions regarding the implications of recovering certain microorganisms from patients. For example, some bacterial commensals of the vagina accept been associated with neonatal pneumonia, demonstrating that the aforementioned organism can be a commensal in i host and a pathogen in some other (10). The recovery of C. albicans from multiple sites presents the vexing question of whether it is a reflection of colonization or infection. Similarly, it is often very difficult to distinguish between colonization and infection when gram-negative microbes, such as Pseudomonas spp., are recovered from individuals on ventilator support in intensive care units. In patients with chronic obstructive lung disease, a variety of well-recognized bacterial pathogens can be continuously isolated from the lower airways, even betwixt disease exacerbations (50). Business organisation that colonization can lead to higher rates of clinical disease and transmission to others underlies the exercise of administering antimicrobial prophylaxes to contacts of individuals with North. meningitidis and S. pyogenes infections (47).
In clinical medicine, the presence of an infection mostly constitutes a requirement for therapy. In the absence of objective information indicative of infection, treatment of colonization is usually avoided due to its cost and the risk of adverse reactions and of induction of microbial resistance. The standard definitions of infection and colonization are not helpful clinically in determining the significance of the isolation of certain microbes from wounds and body sites that are normally sterile (49). At nowadays, efforts to institute guidelines for the treatment of states of microbial colonization in the infirmary setting are express past an inadequate agreement of the pathogenesis of colonization and the aspects of the host-microbe human relationship that influence the development of infection after colonization. This has probably fostered empiricism in the direction of infectious diseases that may accept significant deleterious consequences for patient intendance and increase the emergence of resistant strains (half dozen).
USE OF Harm FRAMEWORK TO CLARIFY Lexicon
Changes in the epidemiology of infectious diseases, including an increased prevalence of emerging and nosocomial infections, increased numbers of hosts with immune impairment, and new basic scientific information about microbial pathogenesis, have rendered parts of the dictionary inadequate and in demand of revision. The absence of a unified framework to serve as a theoretical foundation for the lexicon has resulted in the persistent utilise of terms that emphasize differences between microbes and specific microbial attributes at the expense of common themes. A major event has been fragmentation in the field, such that the disciplines of bacteriology, mycology, parasitology, and virology are increasingly insular, despite the fact that all study like questions. In our view, this problem may be ameliorated past an integrated theory of microbial pathogenesis that considers the contributions of both host and pathogen in this process. Our outset arroyo to this conundrum was to introduce the concept that host damage is the relevant outcome in host-microbe interactions and to propose a pathogen classification scheme based on the ability of a microbe to crusade damage as a function of the host'due south immune response (7). That framework grouped microbes based on their power to inflict damage equally a function of the host response, irrespective of their phylogenetic derivation. By focusing on damage instead of pathogen or host, mutual themes in microbial pathogenesis became more apparent. The same framework can be used to analyze the dictionary of microbial pathogenesis.
INTEGRATED LEXICON TO DESCRIBE HOST-PATHOGEN INTERACTION
Nosotros propose that the outcome of host-pathogen interaction is determined by the nature of the damage that results from the host-microbe relationship (Fig. one). This concept is based upon three assumptions. First, the acquisition of a microbe past a host can result in some course of damage to host tissues that elicits a microbe-specific immune response (7). Second, except for congenitally acquired microbes, mammalian hosts are built-in without a meaning microbial burden and the initial acquisition of microbial flora therefore results from infection. Third, the corporeality and blazon of damage that occurs during the initial and/or ongoing host-microbe relationship determines the outcome of the host-microbe relationship. This view is consistent with the danger hypothesis proposed by Matzinger (30) and others (22) that allowed responses arise from the detection of danger signals produced by microbes or infected tissues. Thus, we propose that host damage is often a requirement for the induction of a pathogen-specific immune response and that the constancy, type, and magnitude of damage that ensues should course the basis of the lexicon of microbial pathogenesis.
Event of the host-microbe interaction in the context of the damage framework proposed in reference seven. The diverse states shown in this figure are defined in Table two. Double-headed arrows signal conditions where there may be variable amounts of harm. Single-headed arrows indicate the post-obit. A, acquisition of a microbe can exist followed by emptying through concrete defenses or immune mechanisms. B, acquisition of certain microbes results in damage and disease in sure hosts. C, certain commensal microbes can crusade disease if the state of commensalism is disturbed by allowed impairment or alterations of the host microbial flora (e.g., C. albicans can cause pharyngeal candidiasis and vaginal candidiasis in the settings of immune suppression and antibiotic use, respectively). D, the country of colonization may exist terminated by an immune response (e.g., transient nasopharyngeal railroad vehicle of Northward. meningiditis or S. pneumoniae). The trigger for the immune response is not well understood, but may occur afterwards the impairment threshold is reached. E, the state of colonization may atomic number 82 to disease if sufficient damage ensues from the interaction. The damage may be host-mediated, pathogen-mediated, or both. F, the state of colonization may lead to a state of persistence (chronicity and latency), whereby the immune response is unable to eradicate the infection despite continued damage (e.grand., latent M. tuberculosis or Histoplasma capsulatum infection in tissue granuloma). Thou, an immune response or therapy may eradicate the infection but this does not always end disease, because the damage may be irreversible (e.g., poliomyelitis) or keep through immunological mechanisms (eastward.g., reactive arthropathies). H, if sufficient impairment is incurred equally a result of the host-microbe interaction, death ensues. I, persistent infections may reactivate and cause overt disease (e.thou., reactivation tuberculosis).
Infection.
The word infection is from the Latin word infiere, which means to dye, stain, corrupt, or spoil and has been associated with disease since antiquity (17, 40). Ancient usage of this term includes the idea that disease was caused by invisible agents that entered the body (17). However, whereas some authors consider an infection to be the outcome of a tissue invasion (26, 49), others have used the give-and-take to include initial contact between parasite and host (42, 55, 56) and others accept defined the term to include disease causation (4, 15).
We advise to define infection as the acquisition of a microbe past a host (Table 2; Fig. 1). Eradication of the microbe by the host can occur at kickoff contact, thus bypassing infection, by nonimmune (due east.one thousand., mechanical) mechanisms and subsequently by immunologic mechanisms. Successful immune responses and/or antimicrobial therapy reduces the amount of continuing damage acquired by the microbe to a level that is insignificant. Notably, eradication of a microbe may not eliminate clinical disease, since immunological damage to the host may persist following a successful antipathogen response, e.g., rheumatic heart disease following streptococcal pharyngitis and reactive arthritis following gastrointestinal infection with certain leaner. The definition of infection proposed here avoids the defoliation surrounding the synonymous use of infection and disease and is consequent with several of the definitions listed in Table ane and the ancient origins of the word (see in a higher place). Furthermore, the concept that clinical affliction is associated with damage and the induction of an immune response is consistent with the historical concept of immunologic proof of causation and applies to different types of microbes (12) and to the currently accepted prototype that allowed cells must interact directly with microbes or their antigens to produce an antigen-specific response.
Table 2
Proposed revisions to terminology of microbial pathogenesis in the context of the damage framework
| Term | Revised definition |
|---|---|
| Carrier state | Synonymous with colonization |
| Chronicity | Synonymous with persistence |
| Colonization | A state of infection that results in a continuum of damage from none to cracking, with the latter leading to the induction of host responses that could eliminate or retain the microbe, or progress to chronicity or disease; for organisms that induce no damage during infection this country is indistinguishable from commensalism |
| Commensal | Microbe that induces either no harm or clinically inapparent damage later principal infection; a state that is thought to be established early on in life |
| Commensalism | A state of infection that results in either no impairment or clinically inapparent harm to the host, though it tin can elicit an immune response |
| Harm | The break of normal tissue structure and/or function of the host that applies at the cellular, tissue, and organ levels (necrosis, apoptosis, mutation, synaptic blockage, and malignant transformation are examples of damage at the cellular level; granulomatous inflammation, fibrosis, tumor are examples of impairment at the tissue level; Ductal obstruction is an example of damage at the organ level); the presence of a microbe-specific immune response may exist indicative of a heretofore unrecognized manifestation of damage |
| Elimination | Removal of the microbe from the boundaries of the host by either physical factors, interference by host flora, an allowed response, or therapy |
| Infection | Conquering of a microbe by host; most infections are followed past multiplication of the microbe in the host, but this is non universal because some helminth infections can involve a single organism that does not replicate in the host |
| Communicable diseases | The clinical manifestation of harm that results from a host-microbe interaction |
| Latency | Synonymous with persistence, this term is frequently used to draw infections that are asymptomatic over long periods of fourth dimension but can evolve into overt disease |
| Persistence | A country of infection in which the host response does non eliminate the microbe, resulting in continued damage over time; persistence may evolve into overt affliction, depending on the residue of the host-microbe interaction (Fig. 1) |
| Pathogen | A microbe capable of causing host damage (every bit defined in reference 7) |
| Symbiosis and mutualism | A state of infection whereby both the host and the microbe benefit as a consequence of infection |
Commensalism.
The word commensal (from the Latin roots com meaning with, mensa significant table, and al meaning pertaining to) can exist translated "eating at the same table" (21). Our suggested revision to the definition of commensal is in the spirit of the original significant of the word. Commensalism is divers as a host-microbial interaction that does not upshot in perceptible, ongoing, and/or persistent host damage (Fig. 1; Table 2). Nevertheless, it is notable that this may non exist absolute, since the initial acquisition of commensal organisms may elicit impairment in some hosts. For example, Escherichia coli is acquired shortly after birth and this run into places some infants at risk for E. coli meningitis during the first month of life (reviewed in reference 46). Similarly, symptomatic infections with C. albicans tin occur in the get-go year of life. Microbes that found themselves early on in life encounter an immature immune arrangement that may be unable to mount effective responses. The latter raises the possibility that immunologic immaturity may facilitate the establishment of a commensal state, but more than work is needed to examine the validity of this concept. Nevertheless, the microbes that comprise the normal microflora of the oral, respiratory, and gastrointestinal tracts provide important stimuli for the development of immunity. Commensal microbes are antigenic and can elicit antibody responses (reviewed in reference 46). Information technology is not known whether these immune responses reverberate the occurrence of an unidentified form of damage to the host. Commensals besides synthesize metabolites that are essential nutrients for the host (reviewed in reference 46) and protect the host by physically and metabolically preventing the acquisition and establishment of more pathogenic microorganisms. In view of the fact that the endogenous microbial flora plays a protective function against more than-pathogenic microbes, conditions that compromise the viability of this flora may damage the host, as evidenced by the ascertainment that disruption of endogenous microflora by antimicrobials predisposes to sure infectious diseases. Hence, the endogenous microflora, collectively chosen commensals, is acquired past infection, stimulates the immune system upon acquisition, and plays a beneficial role throughout life. Interestingly, it may be hard to distinguish host and microbe, as illustrated by the fact that the DNA of endogenous retroviruses comprises 1% of the human genome (45). In fact, upon noting that there are 10thirteen cells in the human body and x14 to 10fifteen private microbes, Isenberg profoundly asked who parasitizes whom (twenty).
Colonization, persistence, and affliction.
The word illness derives from Onetime French and originally unsaid a deviation from normal or easy living (xl). Here, nosotros ascertain affliction as a clinical manifestation of damage that results from host-microbe interaction. Colonization is divers as a state in which the microbe may exist present in the host for a variable duration of time. In a setting in which the level of damage is insignificant, there may exist no distinction betwixt commensalism and colonization. However, in keeping with historical definitions, the establishment of the commensal land generally occurs early in life. When the damage associated with prolonged states of colonization induces a new state in the host, e.1000., a granuloma post-obit infection with Mycobacterium tuberculosis, the outcome is persistence (Fig. 1). Thus, commensalism, colonization, and persistence are separate outcomes of infection, but they are potentially linked and continuous based upon the consecration of damage. Therefore, the damage experienced past the host during colonization is office of a continuum which spans from none, as with that induced by a commensal, to meaning, as with that induced by a pathogen (Fig. i). Colonization is a state characterized past microbial replication that may induce host impairment and trigger a microbe-specific allowed response which in turn could eradicate or contain the microbe. If the host immune response, antimicrobial therapy, and/or vaccination succeed in eradicating the microbe, the state of colonization is eliminated. If the microbe is not eliminated, a state of persistence may ensue. Progressive damage that results from this country may atomic number 82 to disease and death. Thus, colonization and its modified versions, namely, persistence and disease, represent the connected presence of a microbe(due south) in the host with a variable caste of, simply continued, host damage.
SYNTHESIS OF REVISED LEXICON
We propose that the outcomes of infection represent a continuum and that the occurrence of 1 versus another is the result of an coaction between host and microbial factors for a item microbe in a particular host. This coaction permits some microbes to be commensals in some hosts merely to cause disease in others. Therefore, as discussed in our previous review, the aspect of microbial virulence and the stardom betwixt pathogens and nonpathogens are critically dependent on host factors (7). Hither, we reason that the consequence of an infection with an organism is also a part of host-microbe interaction. For example, C. albicans is a commensal in normal individuals with intact endogenous flora but a pathogen in some immunosuppressed patients (e.g., those with an immune disturbance), those receiving antibiotics (east.yard., those with a microflora disturbance), and neonates who take immature gastrointestinal tracts and have not yet established their endogenous microbial flora (due east.g., immature hosts). Consistent with this view, it has been proposed that immunologic function determines whether contact with C. albicans results in clearance, colonization, or candidiasis (5).
Notably, the proposed definitions in Table two are consequent with nigh, if not all, of the many definitions already establish in the literature (Table 1), e.grand., our definition of commensal is similar to that of White and Timbury (53), and the word damage is already part of many definitions (Tabular array 1). This review represents an effort to integrate these terms into a unified framework based on the harm-response hypothesis put along previously (7) to produce a simplified lexicon centered upon the event of host-microbe interaction rather than on distinctions between pathogens and nonpathogens. This approach avoids the current problem of definitions that are dependent upon specific microbial or host characteristics and ofttimes require qualification because of the inherent variability amidst the participants in the host-microbe interaction. Thus, an advantage of the proposed lexicon may exist reduced ambiguity.
CONCLUSIONS
This and our previous commodity (7) arose directly from our experiences teaching microbial pathogenesis to graduate and medical students. We have constitute it hard to teach basic concepts of microbial pathogenesis because the terminology is not based on an integrated framework that can exist used to organize the available data or easily conform new data. Nosotros promise that the proposed modifications to the lexicon will stimulate give-and-take and experimentation to support or abnegate existing concepts. Experimental validation for the impairment framework may require the development of more sensitive assays to measure host damage. Current measures of damage that rely on mortality, tissue destruction, or clinical illness may be besides insensitive to characterize host-pathogen interactions that lead to colonization or chronicity. Given the daunting complication of the host-microbe relationship, our suggestions should be considered part of a work in progress that will undoubtedly require additional modifications every bit more data becomes available. Our proposal that damage be used to characterize host-microbe interaction provides a flexible framework to bring order and predictability to the lexicon, since damage is a relevant and potentially quantifiable outcome that can serve as the common denominator for analysis of the issue of host-pathogen interactions.
ACKNOWLEDGMENTS
A.C. is supported by NIH awards AI33774, AI3342, and HL-59842-01 and is a recipient of a Burroughs Wellcome Development Therapeutics Award. Fifty.P. is supported by NIH grant AI35370.
We are grateful to Stephanie Tucker, Bettina Fries, Marta Feldmesser, and Joshua Nosanchuk for critical reading of this manuscript and many helpful suggestions.
Both authors contributed as to this work.
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