Natural resistance to worms exacerbates bovine tuberculosis severity independently of worm coinfection.

Pathogen interactions arising during coinfection can exacerbate disease severity, for example when the immune response mounted against one pathogen negatively affects defense of another. It is also possible that host immune responses to a pathogen, shaped by historical evolutionary interactions between host and pathogen, may modify host immune defenses in ways that have repercussions for other pathogens. In this case, negative interactions between two pathogens could emerge even in the absence of concurrent infection. Parasitic worms and tuberculosis (TB) are involved in one of the most geographically extensive of pathogen interactions, and during coinfection worms can exacerbate TB disease outcomes. Here, we show that in a wild mammal natural resistance to worms affects bovine tuberculosis (BTB) severity independently of active worm infection. We found that worm-resistant individuals were more likely to die of BTB than were nonresistant individuals, and their disease progressed more quickly. Anthelmintic treatment moderated, but did not eliminate, the resistance effect, and the effects of resistance and treatment were opposite and additive, with untreated, resistant individuals experiencing the highest mortality. Furthermore, resistance and anthelmintic treatment had nonoverlapping effects on BTB pathology. The effects of resistance manifested in the lungs (the primary site of BTB infection), while the effects of treatment manifested almost entirely in the lymph nodes (the site of disseminated disease), suggesting that resistance and active worm infection affect BTB progression via distinct mechanisms. Our findings reveal that interactions between pathogens can occur as a consequence of processes arising on very different timescales.

Mortality trajectory analysis reveals the drivers of sex-specific epidemiology in natural wildlife-disease interactions.

In animal populations, males are commonly more susceptible to disease-induced mortality than females. However, three competing mechanisms can cause this sex bias: weak males may simultaneously be more prone to exposure to infection and mortality; being 'male' may be an imperfect proxy for the underlying driver of disease-induced mortality; or males may experience increased severity of disease-induced effects compared with females. Here, we infer the drivers of sex-specific epidemiology by decomposing fixed mortality rates into mortality trajectories and comparing their parameters. We applied Bayesian survival trajectory analysis to a 22-year longitudinal study of a population of badgers (Meles meles) naturally infected with bovine tuberculosis (bTB). At the point of infection, infected male and female badgers had equal mortality risk, refuting the hypothesis that acquisition of infection occurs in males with coincidentally high mortality. Males and females exhibited similar levels of heterogeneity in mortality risk, refuting the hypothesis that maleness is only a proxy for disease susceptibility. Instead, sex differences were caused by a more rapid increase in male mortality rates following infection. Males are indeed more susceptible to bTB, probably due to immunological differences between the sexes. We recommend this mortality trajectory approach for the study of infection in animal populations.

Methodology and preliminary results of a systematic literature review of ante-mortem and post-mortem diagnostic tests for bovine tuberculosis.

A systematic review was conducted to identify studies with data for statistical meta-analyses of sensitivity (Se) and specificity (Sp) of ante-mortem and post-mortem diagnostic tests for bovine tuberculosis (bTB) in cattle. Members of a working group (WG) developed and tested search criteria and developed a standardised two-stage review process, to identify primary studies with numerator and denominator data for test performance and an agreed range of covariate data. No limits were applied to year, language, region or type of test in initial searches of electronic databases. In stage 1, titles and available abstracts were reviewed. References that complied with stage 1 selection criteria were reviewed in entirety and agreed data were extracted from references that complied with stage 2 selection criteria. At stage 1, 9782 references were reviewed and 261 (2.6%) passed through to stage 2 where 215 English language references were each randomly allocated to two of 18 WG reviewers and 46 references in other languages were allocated to native speakers. Agreement regarding eligibility between reviewers of the same reference at stage 2 was moderate (Kappa statistic = 0.51) and a resolution procedure was conducted. Only 119 references (published 1934-2009) were identified with eligible performance estimates for one or more of 14 different diagnostic test types; despite a comprehensive search strategy and the global impact of bTB. Searches of electronic databases for diagnostic test performance data were found to be nonspecific with regard to identifying references with diagnostic test Se or Sp data. Guidelines for the content of abstracts to research papers reporting diagnostic test performance are presented. The results of meta-analyses of the sensitivity and specificity of the tests, and of an evaluation of the methodological quality of the source references, are presented in accompanying papers (Nuñez-Garcia et al., 2017; Downs et al., 2017).

The buffalo co-infection conundrum.

Parasitic worms modulate host immunity, affecting co-infection with Mycobacterium bovis (BTB). Ezenwa and Jolles suggested that anthelmintic treatment reduced BTB-induced mortality, but increased BTB spread. Reduced mortality should be weighed against the risk of increasing pathogen spread when adopting this strategy for human treatment of Mycobacterium tuberculosis, BTB, and HIV.

Epidemiology. Opposite effects of anthelmintic treatment on microbial infection at individual versus population scales.

Parasitic worms modulate host immune responses in ways that affect microbial co-infections. For this reason, anthelmintic therapy may be a potent tool for indirectly controlling microbial pathogens. However, the population-level consequences of this type of intervention on co-infecting microbes are unknown. We evaluated the effects of anthelmintic treatment on bovine tuberculosis (BTB) acquisition, mortality after infection, and pathogen fitness in free-ranging African buffalo. We found that treatment had no effect on the probability of BTB infection, but buffalo survival after infection was ninefold higher among treated individuals. These contrasting effects translated into an approximately eightfold increase in the reproductive number of BTB for anthelmintic-treated compared with untreated buffalo. Our results indicate that anthelmintic treatment can enhance the spread of microbial pathogens in some real-world situations.

Demographic processes drive increases in wildlife disease following population reduction.

Population reduction is often used as a control strategy when managing infectious diseases in wildlife populations in order to reduce host density below a critical threshold. However, population reduction can disrupt existing social and demographic structures leading to changes in observed host behaviour that may result in enhanced disease transmission. Such effects have been observed in several disease systems, notably badgers and bovine tuberculosis. Here we characterise the fundamental properties of disease systems for which such effects undermine the disease control benefits of population reduction. By quantifying the size of response to population reduction in terms of enhanced transmission within a generic non-spatial model, the properties of disease systems in which such effects reduce or even reverse the disease control benefits of population reduction are identified. If population reduction is not sufficiently severe, then enhanced transmission can lead to the counter intuitive perturbation effect, whereby disease levels increase or persist where they would otherwise die out. Perturbation effects are largest for systems with low levels of disease, e.g. low levels of endemicity or emerging disease. Analysis of a stochastic spatial meta-population model of demography and disease dynamics leads to qualitatively similar conclusions. Moreover, enhanced transmission itself is found to arise as an emergent property of density dependent dispersal in such systems. This spatial analysis also shows that, below some threshold, population reduction can rapidly increase the area affected by disease, potentially expanding risks to sympatric species. Our results suggest that the impact of population reduction on social and demographic structures is likely to undermine disease control in many systems, and in severe cases leads to the perturbation effect. Social and demographic mechanisms that enhance transmission following population reduction should therefore be routinely considered when designing control programmes.

Molecular identification of Mycobacterium bovis and the importance of zoonotic tuberculosis in Mexican patients.

SETTING: The epidemiology of zoonotic tuberculosis (ZTB) in humans in Mexico is poorly known. OBJECTIVE: To identify isolates of Mycobacterium bovis in humans and cattle by polymerase chain reaction (PCR), and establish the clinical and epidemiological importance of ZTB in humans. DESIGN: From 1995 to 2009, 124 isolates from patients with TB and 60 isolates from cattle were analysed. PCR identification was performed using the oxy R gene, and the clinical and epidemiological aspects of ZTB in humans were investigated. RESULTS: PCR identified 93 M. bovis isolates: 35 (28%) from the 124 human isolates and 58 (97%) from the 60 cattle isolates. The sensitivity and specificity of the method were 100%. ZTB in the 35 patients presented as extra-pulmonary TB (EPTB) in 74%: 51% were children, 69% had malnutrition, 51% had consumed unpasteurised milk and 6% had contact with animals; 11% were relapses and 31% died. CONCLUSIONS: PCR using the oxy R gene is highly sensitive, specific and rapid for the identification of M. bois. ZTB is a serious public health problem, and presented as EPTB in children with malnutrition and those who had consumed unpasteurised milk. ZTB provokes relapses and a high mortality rate.

Thresholds and stability analysis of models for the spatial spread of a fatal disease.

A simple two-class (susceptibles and infectives) model describing the dynamics of a fatal disease in a variable-size population is presented and analysed. Spatial dependence is introduced into the model by considering two different mechanisms for the geographic spread of the disease: nonlocal interaction between susceptibles and infectives, and migratory spread of the animals. The steady states and their stability for these spatially dependent models are deduced; no spatially heterogeneous steady states were possible. For nonlocal interaction, there were two spatially uniform steady states: the trivial state (no infectives or susceptibles), which was unstable, and the endemic state (constant proportion of the population infected), which was locally asymptotically stable. With migratory spread, the number of spatially uniform steady states was dependent on the boundary conditions imposed. With hostile (Dirichlet) boundary conditions, only the trivial steady state was possible and its local stability found to depend on the rate of diffusion of the total population. With no-flux (Neumann) boundary conditions, the steady states are the trivial and endemic states; these were unstable and locally asymptotically stable, respectively.

Effect of systemic BCG infection in syrian golden hamsters.

The response of Syrian golden hamsters to systemic infection with several doses of Mycobacterium bovis (strain BCG) was assessed. Large numbers of organisms (10(7)), injected intravenously, were lethal for hamsters, whereas all animals survived infection with 10(4) colony-forming units of BCG. Animals responded immunologically to purified protein derivative as assessed by increased footpad swelling and splenic lymphocyte proliferation. The immediate cause of death was a diffuse granulomatous interstitial pneumonia.

The occurrence of Mycobacterium bovis infection in cattle in and around an area subject to extensive badger (Meles meles) control.

The occurrence of Mycobacterium bovis infection in cattle herds during the period 1966-92 in two geographically related areas in South-West England is compared. In one area comprising 104 km2 all badgers were systematically destroyed from 1975-81, after which recolonization was allowed; in the other, comprising 116 km2, small scale, statutory badger removal operations were undertaken from 1975 onwards where specific herds were detected with M. bovis infection. In the area with total clearance, no further incidents with M. bovis isolation occurred from 1982-92. Survival analysis and proportional hazards regression indicated that the risk of herds being identified with infection was less once badgers had been cleared from their neighbourhood, whereas it was greater in herds with 50 or more animals, and once cattle in a herd had responded positively to the tuberculin skin test, even though infection with M. bovis was not confirmed subsequently. The study provides further evidence that badgers represent an important reservoir of M. bovis infection for cattle and that badger control is effective in reducing incidents of cattle infection with M. bovis if action is thorough and recolonization is prevented.

Restoration of T-cell responsiveness by thymosin: development of antituberculous resistance in BCG-infected animals.

T-cell-depleted (adult thymectomized, lethally irradiated, bone marrow-reconstituted [THXB]), sham-thymectomized (XB) and normal control mice were injected daily with 3 mg of calf thymosin for 16 days. On day 8 of the treatment, the mice, together with untreated controls, were infected intravenously with 4 X 10(6) viable Mycobacterium bovis (BCG Montreal). Growth of the BCG in the lungs and spleens was compared quantitatively for up to 100 days. Thymosin treatment reversed the progressive weight loss seen in BCG-infected THXB mice and prevented their death due to the ongoing mycobacteriosis that developed in the T-cell-depleted animal. There was a late-developing anti-mycobacterial response in the thymosin-treated THXB mice, which resulted in a progressive decline in viability for the lung and spleen populations over the 40- to 80-day period, when the corresponding counts for the untreated THXB mice remained relatively constant. The histopathology of the lung and the increased antibacterial activity seen in the thymosin-treated THXB mice correlated with decreased [3H]deoxyribonucleic acid levels seen in the lungs and spleen compared with that present in the T-cell-depleted controls.