How host heterogeneity governs tuberculosis reinfection?

Recurrent episodes of tuberculosis (TB) can be due to relapse of latent infection or exogenous reinfection, and discrimination is crucial for control planning. Molecular genotyping of Mycobacterium tuberculosis isolates offers concrete opportunities to measure the relative contribution of reinfection in recurrent disease. Here, a mathematical model of TB transmission is fitted to data from 14 molecular epidemiology studies, enabling the estimation of relevant epidemiological parameters. Meta-analysis reveals that rates of reinfection after successful treatment are higher than rates of new TB, raising an important question about the underlying mechanism. We formulate two alternative mechanisms within our model framework: (i) infection increases susceptibility to reinfection or (ii) infection affects individuals differentially, thereby recruiting high-risk individuals to the group at risk for reinfection. The second mechanism is better supported by the fittings to the data, suggesting that reinfection rates are inflated through a population phenomenon that occurs in the presence of heterogeneity in individual risk of infection. As a result, rates of reinfection are higher when measured at the population level even though they might be lower at the individual level. Finally, differential host recruitment is modulated by transmission intensity, being less pronounced when incidence is high.     

B-cell memory and the persistence of antibody responses

Antigens such as viral envelope proteins and bacterial exotoxins induce responses which result in the production of neutralizing antibody. These responses persist for years and provide highly efficient defence against reinfection. During these antibody responses a proportion of participating B cells mutate the genes that encode their immunoglobulin variable regions. This can increase the affinity of the antibody, but can also induce autoreactive B cells. Selection mechanisms operate which allow the cells with high affinity for the provoking antigen to persist, while other B cells recruited into the response die.     

A predominant role for antibody in acquired immunity to chlamydial genital tract reinfection

Acquired immunity to murine Chlamydia trachomatis genital tract reinfection has long been assumed to be solely dependent on cell-mediated immunity. However, in this study, we identify a previously unrecognized protective role for Ab. Immunity develops in Ab-deficient mice following the resolution of primary chlamydial genital infection. Subsequent depletion of CD4+ T cells, but not CD8+ T cells, in those immune Ab-deficient mice before secondary infectious challenge, resulted in an infection that did not resolve. Passive immunization with immune (convalescent) serum conferred a marked level of protective immunity to reinfection, which was characterized by a striking decrease in bacterial shedding, from >100,000 inclusion forming units to fewer than 10 inclusion forming units, and a shortened duration of infection. Furthermore, mAbs to the chlamydial major outer membrane protein and LPS conferred significant levels of immunity to reinfection and reduced chlamydial shedding by >100-fold. Anti-heat shock protein 60 mAb had no protective effect. In contrast to the marked protective efficacy of immune serum on reinfection, the course of primary infection was essentially unaltered by the passive transfer of immune serum. Our results convincingly demonstrate that Abs contribute importantly to immunity to chlamydial genital tract reinfection, and that Ab-mediated protection is highly dependent on CD4+ T cell-mediated adaptive changes that occur in the local genital tract tissues during primary infection. These results impact our understanding of immunity to chlamydial genital infection and may provide important insight into vaccine development.     

Evolution of immunological memory and the regulation of competition between pathogens

Memory is a central characteristic of immune responses. It is defined as an elevated number of specific immune cells that remain after resolution of infection and can protect the host against reinfection. The evolution of immunological memory is subject to debate. The advantages of memory discussed so far include protection from reinfection, control of chronic infection, and the transfer of immune function to the next generation. Mathematical models are used to identify a new force that can drive the evolution of immunological memory: the duration of memory can regulate the degree of competition between different pathogens. While a long duration of memory provides lasting protection against reinfection, it may also allow an inferior pathogen species to persist. This can be detrimental for the host if the inferior pathogen is more virulent. On the other hand, a shorter duration of memory ensures that an inferior pathogen species is excluded. This can be beneficial for the host if the inferior pathogen is more virulent. Thus, while in the absence of pathogen diversity memory is always expected to evolve to a long duration, under specific circumstances, memory can evolve toward shorter durations in the presence of pathogen diversity.     

Longitudinal studies on human schistosomiasis

A major difficulty in understanding the epidemiology of human schistosomiasis has been to distinguish between acquired immunity and reduced exposure as possible reasons for an observed decline, in older individuals, of levels of superinfection or of reinfection after chemotherapy. A series of studies of Schistosoma mansoni infections in Kenya has been undertaken to approach this problem, by investigation of intensities of reinfection after treatment of individuals whose levels of contact with contaminated water is subsequently observed. Intensities of reinfection are highest among younger children, thereafter declining sharply. This decline can be attributed only in part to age-related changes in the duration and nature of exposure; there is also evidence for the development of an acquired resistance to reinfection that is dependent both on age and on previous experience of infection, and that may be immunologically mediated. Evidence has been obtained that the slow development of this acquired immunity with age may be associated with the early development and subsequent slow decline of inappropriate immune responses that 'block' the effect of potentially protective responses. Implications of these findings for immunological intervention through vaccination are discussed.     

Differing roles of inflammation and antigen in T cell proliferation and memory generation

Recent studies have demonstrated that viral and bacterial infections can induce dramatic in vivo expansion of Ag-specific T lymphocytes. Although presentation of Ag is critical for activation of naive T cells, it is less clear how dependent subsequent in vivo T cell proliferation and memory generation are upon Ag. We investigated T cell expansion and memory generation in mice infected alternately with strains of Listeria monocytogenes that contained or lacked an immunodominant, MHC class I-restricted T cell epitope. We found substantial differences in the responses of effector and memory T cells to inflammatory stimuli. Although effector T cells undergo in vivo expansion in response to bacterial infection in the absence of Ag, memory T cells show no evidence for such bystander activation. However, Ag-independent expansion of effector T cells does not result in increased memory T cell frequencies, indicating that Ag presentation is critical for effective memory T cell generation. Early reinfection of mice with L. monocytogenes before the maximal primary T cell response induces typical memory expansion, suggesting that the capacity for a memory T cell response exists within the primary effector population. Our findings demonstrate that T cell effector proliferation and memory generation are temporally overlapping processes with differing requirements for Ag.     

Parasites and immune responses: memory illusion?

Immunological memory responses to intracellular protozoa and extracellular helminths govern host resistance and susceptibility to reinfection. Humans and livestock living in parasitic disease endemic regions face continuous exposure from a very early age that often leads to asymptomatic chronic infection over their entire lifespan. Fundamental immunological studies suggest that the generation of T-cell memory is driven by tightly coordinated innate and adaptive cellular immune responses rapidly triggered following initial host infection. A key distinguishing feature of immune memory maintenance between the majority of parasitic diseases and most bacterial or viral diseases is long-term antigen persistence. Consequently, functional parasite immune memory is in a continuous, dynamic flux between activation and deactivation producing functional parasite killing or functional memory cell death. In this sense, T-cell immune memory can be regarded as "memory illusion." Furthermore, due to the finite capacity of memory lymphocytes to proliferate, continuous parasite antigen stimulation may exceed a threshold level at some point in the chronically infected host. This may result in suboptimal effector immune memory leading to host susceptibility to reinfection, or immune dysregulation yielding disease reactivation or immune pathology. The goal of this review is to highlight, through numerous examples, what is currently known about T-cell immune memory to parasites and to provide compelling hypotheses on the survival and maintenance of parasite "memory illusion." These novel concepts are discussed in the context of rationale parasite vaccine design strategies.     

Endosymbiosis of Chlorella species to the ciliate Paramecium bursaria alters the distribution of the host’s trichocysts beneath the host cell cortex

Each symbiotic Chlorella of the ciliate Paramecium bursaria is enclosed in a perialgal vacuole membrane derived from the host digestive vacuole membrane. Alga-free paramecia and symbiotic algae can grow independently. Mixing them experimentally can cause reinfection. Earlier, we reported that the symbiotic algae appear to push the host trichocysts aside to become fixed beneath the host cell cortex during the algal reinfection process. Indirect immunofluorescence microscopy with a monoclonal antibody against the trichocysts demonstrates that the trichocysts change their locality to form algal attachment sites and decrease their density beneath the host cell cortex through algal reinfection. Transmission electron microscopy to detect acid phosphatase activity showed that some trichocysts near the host cell cortex are digested by the host lysosomal fusion during algal reinfection. Removal of algae from the host cell using cycloheximide recovers the trichocyst's arrangement and number near the host cell cortex. These results indicate that symbiotic algae compete for their attachment sites with preexisting trichocysts and that the algae have the ability to ensure algal attachment sites beneath the host cell cortex.     

Chinchilla and murine models of upper respiratory tract infections with respiratory syncytial virus

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants and the elderly. While the primary infection is the most serious, reinfection of the upper airway throughout life is the rule. Although relatively little is known about either RSV infection of the upper respiratory tract or host mucosal immunity to RSV, recent literature suggests that RSV is the predominant viral pathogen predisposing to bacterial otitis media (OM). Herein, we describe mouse and chinchilla models of RSV infection of the nasopharynx and Eustachian tube. Both rodent hosts were susceptible to RSV infection of the upper airway following intranasal challenge; however, the chinchilla proved to be more permissive than the mouse. The chinchilla model will likely be extremely useful to test the role of RSV in bacterial OM and the efficacy of RSV vaccine candidates designed to provide mucosal and cytotoxic T-lymphocyte immunity. Ultimately, we hope to investigate the relative ability of these candidates to potentially protect against viral predisposal to bacterial OM.     

Successful reinfection of chronically infected mice by a different Toxoplasma gondii genotype

It is generally assumed that primary infection by Toxoplasma gondii protects from reinfection. A recent study using a murine model has questioned this dogma using indirect procedures to detect the reinfecting strain. We have reinvestigated this issue using a transfected strain of T. gondii (Prugniaud beta galactosidase: Pru beta gal) which expresses Escherichia coli beta-galactosidase. Detection of enzyme activity on fixed parasites allows a direct distinction between transfected and untransfected strains. We have found that in OF1 mice primary infection with the 76 K strain of T. gondii fully protects mice against tissue cyst production upon reinfection with the Pru beta gal T. gondii strain whereas primary infection with the Pru beta gal T. gondii strain does not impair tissue cyst formation upon reinfection with the Ned strain of T. gondii, which belongs to another T. gondii genotype. These results suggest that the immune protection conferred by one strain of T. gondii can be breached by reinfection with a strain belonging to another genotype; which can have significant consequences in human or veterinary medicine.     

The reinfection threshold promotes variability in tuberculosis epidemiology and vaccine efficacy

Population patterns of infection are determined largely by susceptibility to infection. Infection and vaccination induce an immune response that, typically, reduces susceptibility to subsequent infections. With a general epidemic model, we detect a 'reinfection threshold', above which reinfection is the principal type of transmission and, consequently, infection levels are much higher and vaccination fails. The model is further developed to address human tuberculosis (TB) and the impact of vaccination. The bacille Calmette-Guérin (BCG) is the only vaccine in current use against TB, and there is no consensus about its usefulness. Estimates of protection range from 0 to 80%, and this variability is aggravated by an association between low vaccine efficacy and high prevalence of the disease. We propose an explanation based on three postulates: (i) the potential for transmission varies between populations, owing to differences in socio-economic and environmental factors; (ii) exposure to mycobacteria induces an immune response that is partially protective against reinfection; and (iii) this protection is not significantly improved by BCG vaccination. These postulates combine to reproduce the observed trends, and this is attributed to a reinfection threshold intrinsic to the transmission dynamics. Finally, we demonstrate how reinfection thresholds can be manipulated by vaccination programmes, suggesting that they have a potentially powerful role in global control.     

On the role of reinfection in the transmission of infectious diseases

We introduce a spatial stochastic model for the spread of tuberculosis. After a primary infection, an individual may become sick (and infectious) through an endogenous reinfection or through an exogenous reinfection. We show that even in the absence of endogenous reinfection an epidemic is possible if the exogenous reinfection parameter is high enough. This is in sharp contrast with what happens for a mean field model corresponding to our spatial stochastic model.     

Implications of partial immunity on the prospects for tuberculosis control by post-exposure interventions

One-third of the world population (approximately 2 billion individuals) is currently infected with Mycobacterium tuberculosis, the vast majority harboring a latent infection. As the risk of reactivation is around 10% in a lifetime, it follows that 200 million of these will eventually develop active pulmonary disease. Only therapeutic or post-exposure interventions can tame this vast reservoir of infection. Treatment of latent infections can reduce the risk of reactivation, and there is accumulating evidence that combination with post-exposure vaccines can reduce the risk of reinfection. Here we develop mathematical models to explore the potential of these post-exposure interventions to control tuberculosis on a global scale. Intensive programs targeting recent infections appear generally effective, but the benefit is potentially greater in intermediate prevalence scenarios. Extending these strategies to longer-term persistent infections appears more beneficial where prevalence is low. Finally, we consider that susceptibility to reinfection is altered by therapy, and explore its epidemiological consequences. When we assume that therapy reduces susceptibility to subsequent reinfection, catastrophic dynamics are observed. Thus, a bipolar outcome is obtained, where either small or large reductions in prevalence levels result, depending on the rate of detection and treatment of latent infections. By contrast, increased susceptibility after therapy may induce an increase in disease prevalence and does not lead to catastrophic dynamics. These potential outcomes are silent unless a widespread intervention is implemented.     

The enhancement or prevention of airway hyperresponsiveness during reinfection with respiratory syncytial virus is critically dependent on the age at first infection and IL-13 production

Respiratory syncytial virus (RSV) infection in early life is suspected to play a role in the development of post-bronchiolitis wheezing and asthma. Reinfection is common at all ages, but factors that determine the development of altered airway function after reinfection are not well understood. This study was conducted in a mouse model to define the role of age in determining the consequences on airway function after reinfection. Mice were infected shortly after birth or at weaning and were reinfected 5 wk later, followed by assessment of airway function, airway inflammation, and lung histopathology. Infection of mice at weaning elicited a protective airway response upon reinfection. In this age group, reinfection resulted in increased airway inflammation, but without development of airway hyperresponsiveness (AHR) or eosinophilia and decreased IL-13 levels. By contrast, neonatal infection failed to protect the airways and resulted in enhanced AHR after reinfection. This secondary response was associated with the development of airway eosinophilia, increased IL-13 levels, and mucus hyperproduction. Both CD4- and CD8-positive T cells were a source of IL-13 in the lung, and inhibition of IL-13 abolished AHR and mucus production in these mice. Inoculation of UV-inactivated virus failed to elicit these divergent responses to reinfection, emphasizing the requirement for active lung infection during initial exposure. Thus, neonatal RSV infection predisposes to the development of airway eosinophilia and enhanced AHR via an IL-13-dependent mechanism during reinfection, whereas infection at a later age protects against the development of these altered airway responses after reinfection.     

Retrotransposition of Nonviral RNAs in an Avian Packaging Cell Line

Retroviruses produced from the quail packaging cell line SE21Q1b predominantly contain cellular RNAs instead of viral RNAs. These RNAs can be reverse transcribed and integrated into the genomes of newly infected cells and are thereafter referred to as newly formed retrogenes. We investigated whether retrogene formation can occur within SE21Q1b cells themselves and whether this occurs intracellularly or via extracellular reinfection. By using packaging cell line mutants derived from the SE21Q1b provirus and selectable reporter constructs, we found that the process requires envelope glycoproteins and a retroviral packaging signal. Our results suggest that extracellular reinfection is the primary route of retrotransposition of nonviral RNAs.     

Antigen-specific responses accelerate bacterial clearance in the bladder

Urinary tract infections (UTIs) cause patient morbidity and have a substantial economic impact. Half of all women will suffer a UTI at least once, and 25% of these women will have recurrent infections. That 75% of previously infected women do not become reinfected strongly suggests a role for an adaptive immune response. The goal of this study was to characterize the adaptive immune responses to uropathogenic Escherichia coli (UPEC), the predominant uropathogen. A novel murine model of UTI reinfection was developed using the prototypic cystitis UPEC isolate NU14 harboring a plasmid encoding OVA as a unique antigenic marker. Bacterial colonization of the bladder was quantified following one or more infections with NU14-OVA. Animals developed anti-OVA serum IgG and IgM titers after the initial infection and marked up-regulation of activation markers on splenic T cells. We observed a 95% reduction in bacterial colonization upon reinfection, and splenic leukocytes showed Ag-specific proliferation in vitro. Adoptive transfer of splenic T cells or passive transfer of serum from previously infected mice protected naive syngeneic mice from UPEC colonization. These findings support our hypothesis that adaptive immune responses to UPEC protect the bladder from reinfection and form the basis of understanding susceptibility to recurrent UTI in women.     

Recurrent Invasive Pneumococcal Disease in Children: Underlying Clinical Conditions,and Immunological and Microbiological Characteristics

Purpose

Clinical, immunological and microbiological characteristics of recurrent invasive pneumococcal disease (IPD) in children were evaluated, differentiating relapse from reinfection, in order to identify specific risk factors for both conditions.

Methods

All patients <18 years-old with recurrent IPD admitted to a tertiary-care pediatric center from January 2004 to December 2011 were evaluated. An episode of IPD was defined as the presence of clinical findings of infection together with isolation and/or pneumococcal DNA detection by Real-Time PCR in any sterile body fluid. Recurrent IPD was defined as 2 or more episodes in the same individual at least 1 month apart. Among recurrent IPD, we differentiated relapse (same pneumococcal isolate) from reinfection.

Results

593 patients were diagnosed with IPD and 10 patients died. Among survivors, 23 episodes of recurrent IPD were identified in 10 patients (1.7%). Meningitis was the most frequent form of recurrent IPD (10 episodes/4 children) followed by recurrent empyema (8 episodes/4 children). Three patients with recurrent empyema caused by the same pneumococcal clone ST306 were considered relapses and showed high bacterial load in their first episode. In contrast, all other episodes of recurrent IPD were considered reinfections. Overall, the rate of relapse of IPD was 0.5% and the rate of reinfection 1.2%. Five out of 7 patients with reinfection had an underlying risk factor: cerebrospinal fluid leak (n = 3), chemotherapy treatment (n = 1) and a homozygous mutation in MyD88 gene (n = 1). No predisposing risk factors were found in the remainder.

Conclusions

recurrent IPD in children is a rare condition associated with an identifiable risk factor in case of reinfection in almost 80% of cases. In contrast, recurrent IPD with pleuropneumonia is usually a relapse of infection.     

The Risk of Tuberculosis Reinfection Soon after Cure of a First Disease Episode Is Extremely High in a Hyperendemic Community

Elevated rates of reinfection tuberculosis in various hyperendemic regions have been reported and, in particular, it has been shown that in a high-incidence setting near Cape Town, South Africa, the rate of reinfection tuberculosis (TB) disease after cure of a previous TB disease episode is about four times greater than the rate of first-time TB disease. It is not known whether this elevated rate is caused by a high reinfection rate due, for instance, to living circumstances, or a high rate of progress to disease specific to the patients, or both. In order to address that question we analysed an extensive data set from clinics attended by TB patients in the high-incidence setting near Cape Town, South Africa and found that, in fact, the (average) rate of reinfection (as opposed to the rate of reinfection disease) after cure of a previous TB disease episode is initially about 0.85 per annum. This rate diminishes rapidly over time and after about ten years this rate is similar to the rate of infection in the general population. Also, the rate of progress to disease after reinfection is initially high but declines in subsequent years down to the figure typical for the general population. These findings suggest that the first few months after cure of a TB disease episode form a critical period for controlling reinfection disease in a hyperendemic setting and that monitoring such cured patients could pre-empt a reinfection progressing to active disease.     

Evidence for frequent reinfection with human immunodeficiency virus type 1 of a different subtype

A major premise underlying current human immunodeficiency virus type 1 (HIV-1) vaccine approaches is that preexisting HIV-1-specific immunity will block or reduce infection. However, the recent identification of several cases of HIV-1 reinfection suggests that the specific immune response generated for chronic HIV-1 infection may not be adequate to protect against infection by a second HIV-1 strain. It has been unclear, though, whether these individuals are representative of the global epidemic or are rare cases. Here we show that in a population of high-risk women, HIV-1 reinfection occurs almost as commonly as first infections. The study was designed to detect cases of reinfection by HIV-1 of a different subtype and thus captured cases where there was considerable diversity between the first and second strain. In each case, the second virus emerged approximately 1 year after the first infection, and in two cases, it emerged when viral levels were high, suggesting that a well-established HIV-1 infection may provide little benefit in terms of immunizing against reinfection, at least by more-divergent HIV-1 variants. Our findings indicate an urgent need for studies of larger cohorts to determine the incidence and timing of both intersubtype and intrasubtype reinfection.     

High Rates of Hepatitis C Virus Reinfection and Spontaneous Clearance of Reinfection in People Who Inject Drugs: A Prospective Cohort Study

Hepatitis C virus reinfection and spontaneous clearance of reinfection were examined in a highly characterised cohort of 188 people who inject drugs over a five-year period. Nine confirmed reinfections and 17 possible reinfections were identified (confirmed reinfections were those genetically distinct from the previous infection and possible reinfections were used to define instances where genetic differences between infections could not be assessed due to lack of availability of hepatitis C virus sequence data). The incidence of confirmed reinfection was 28.8 per 100 person-years (PY), 95%CI: 15.0-55.4; the combined incidence of confirmed and possible reinfection was 24.6 per 100 PY (95%CI: 16.8-36.1). The hazard of hepatitis C reinfection was approximately double that of primary hepatitis C infection; it did not reach statistical significance in confirmed reinfections alone (hazard ratio [HR]: 2.45, 95%CI: 0.87-6.86, p=0.089), but did in confirmed and possible hepatitis C reinfections combined (HR: 1.93, 95%CI: 1.01-3.69, p=0.047) and after adjustment for the number of recent injecting partners and duration of injecting. In multivariable analysis, shorter duration of injection (HR: 0.91; 95%CI: 0.83-0.98; p=0.019) and multiple recent injecting partners (HR: 3.12; 95%CI: 1.08-9.00, p=0.035) were independent predictors of possible and confirmed reinfection. Time to spontaneous clearance was shorter in confirmed reinfection (HR: 5.34, 95%CI: 1.67-17.03, p=0.005) and confirmed and possible reinfection (HR: 3.10, 95%CI: 1.10-8.76, p-value=0.033) than primary infection. Nonetheless, 50% of confirmed reinfections and 41% of confirmed or possible reinfections did not spontaneously clear. Conclusions: Hepatitis C reinfection and spontaneous clearance of hepatitis C reinfection were observed at high rates, suggesting partial acquired natural immunity to hepatitis C virus. Public health campaigns about the risks of hepatitis C reinfection are required.