Human-to-Cattle Mycobacterium tuberculosis Complex Transmission in the United States.

The Mycobacterium tuberculosis complex (MTBC) species includes both M. tuberculosis, the primary cause of human tuberculosis (TB), and M. bovis, the primary cause of bovine tuberculosis (bTB), as well as other closely related Mycobacterium species. Zoonotic transmission of M. bovis from cattle to humans was recognized more than a century ago, but transmission of MTBC species from humans to cattle is less often recognized. Within the last decade, multiple published reports from around the world describe human-to-cattle transmission of MTBC. Three probable cases of human-to-cattle MTBC transmission have occurred in the United States since 2013. In the first case, detection of active TB disease (M. bovis) in a dairy employee in North Dakota prompted testing and ultimate detection of bTB infection in the dairy herd. Whole genome sequencing (WGS) demonstrated a match between the bTB strain in the employee and an infected cow. North Dakota animal and public health officials concluded that the employee's infection was the most likely source of disease introduction in the dairy. The second case involved a Wisconsin dairy herd with an employee diagnosed with TB disease in 2015. Subsequently, the herd was tested twice with no disease detected. Three years later, a cow originating from this herd was detected with bTB at slaughter. The strain in the slaughter case matched that of the past employee based on WGS. The third case was a 4-month-old heifer calf born in New Mexico and transported to Texas. The calf was TB tested per Texas entry requirements and found to have M. tuberculosis. Humans are the suspected source of M. tuberculosis in cattle; however, public health authorities were not able to identify an infected human associated with the cattle operation. These three cases provide strong evidence of human-to-cattle transmission of MTBC organisms and highlight human infection as a potential source of introduction of MTBC into dairy herds in the United States. To better understand and address the issue, a multisectoral One Health approach is needed, where industry, public health, and animal health work together to better understand the epidemiology and identify preventive measures to protect human and animal health.

Cost-benefit analysis of vaccination against Mycobacterium avium ssp. paratuberculosis in dairy cattle, given its cross-reactivity with tuberculosis tests.

Johne's disease (JD), or paratuberculosis, is a chronic enteric disease of ruminants, caused by infection with Mycobacterium avium ssp. paratuberculosis (MAP). Johne's disease causes considerable economic losses to the US dairy industry, estimated to be over $200 million annually. Available control strategies include management measures to improve calf hygiene, test-and-cull strategies, and vaccination. Although the first 2 strategies have shown to reduce the prevalence of MAP, they require dedicated and long-term efforts from dairy producers, with often relatively slow progress. As a result, uptake of both strategies has not been as wide as expected given the economic benefits especially of improved hygiene. Vaccination has also been found to reduce the prevalence and economic losses of JD, but most economic estimates have been based on simulation of hypothetical vaccines. In addition, if an animal is vaccinated, cross-reactivity between MAP antibodies and bovine tuberculosis (BTB) antigens may occur, decreasing the specificity of BTB tests. Therefore, MAP vaccination would cause additional indirect costs to the BTB surveillance and control program. The objective of the present study was to use data from a MAP vaccine trial together with an epidemiologic and economic model to estimate the direct on-farm benefits of MAP vaccination and to estimate the indirect costs of MAP vaccination due to the cross-reactivity with BTB tests. Direct economic benefits of MAP vaccination were estimated at $8.03 (90% predictive interval: -$25.97 to $41.36) per adult animal per year, all accruing to the dairy producers. This estimate is likely an underestimation of the true direct benefits of MAP vaccination. In addition, indirect economic costs due to cross-reactivity were $2.14 per adult animal per year, making MAP vaccination economically attractive. Only in regions or states with a high frequency of BTB testing (because of, for example, Mycobacterium bovis outbreaks in a wild deer population) and areas where typically small groups of animals are BTB tested would MAP vaccination not be economically attractive.

Paratuberculosis vaccination.

One vaccine, Mycopar, is licensed for use in US cattle. The vaccine reduces clinical disease and fecal shedding of Mycobacterium avium subsp. paratuberculosis (MAP). The vaccine is indicated for use in herds with a high MAP infection prevalence or herds with limited resources for implementing paratuberculosis control measures. In heavily infected herds, a combination of vaccination and disease control measures can help protect susceptible young stock while reducing environmental burdens and limiting MAP transmission. There are regulatory restrictions on use of the vaccine and practitioners must consult their state veterinarian for guidance. Vaccines used in other countries have been widely adopted in Johne's disease control programs for small ruminants.

Equine platelet CD62P (P-selectin) expression: a phenotypic and morphologic study.

Acute inflammatory diseases, such as colic, septicemia and endotoxemia are common in equines and have been shown to be correlated to vascular injury and thrombosis. In humans with similar thrombotic conditions, P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1)-mediated platelet-leukocyte adhesion contributes to the pathogenesis of these disorders through the generation of inflammatory mediators and tissue factor. As such, we hypothesized that a P-selectin-PSGL-1 (platelet-leukocyte) interaction, similar to that in humans, may also exist in the horse. The objective of this study was to investigate phenotypic and morphological properties of equine platelet activation with a focus on CD62P (P-selectin) expression and CD62P mediated platelet-leukocyte interactions. To study high levels of platelet activation, we used 1 U/ml thrombin to induce secondary, irreversible aggregation in both human and equine platelets. Addition of glycyl-L-prolyl-L-arginyl-L-proline amide (GPRP) prior to thrombin activation blocked fibrin polymerization, allowing the use of flow cytometry to study alpha-granule expression as a measure of platelet activation. Thrombin activation resulted in high levels of activation, measured as P-selectin expression, in both humans and equines. Interestingly, our research illustrates that in healthy horses, P-selectin is also constitutively expressed on 20-25% of resting platelets. This finding is in direct contrast to humans, in which P-selectin expression is negligible (<5%) in the absence of agonist activation. The high baseline level of P-selectin expression among equine platelets may suggest that they are primed for leukocyte adhesion, possibly resulting in prothrombotic conditions. This phenomenon could be of significant clinical relevance, as it may be related to the rapid clinical decline often seen in equine patients with colic and endotoxemia, where vascular injury and thrombotic complications compromise patient survival. Based on these findings, further investigation into the mechanisms of platelet P-selectin-mediated inflammation and platelet-leukocyte mediated vascular injury in the horse appears warranted.

Impaired Th2 development and increased mortality during Schistosoma mansoni infection in the absence of CD40/CD154 interaction.

The role of CD40/CD154 interaction during infection has primarily focused on pathogens that drive inflammatory Th1 responses. In this study, we show that CD40/CD154 interaction is a fundamental requirement for Th2 response development to the parasitic helminth Schistosoma mansoni. Compared with infected wild-type mice, greatly reduced levels of Th2-associated cytokines were measured both in vitro and in vivo, and no IgE or IgG1 was detected in infected CD154(-/-) mice. In the absence of an overt Th2 response, no exaggerated Th1 response was mounted by CD154(-/-) mice. Infected CD154(-/-) mice suffered severe morbidity and mortality, even though parasitemias in wild-type and CD154(-/-) mice did not differ significantly. These data indicate that CD40/CD154 interaction is required to allow development of a Th2-dominated immune response to S. mansoni and support the view that failure to develop such a response can have fatal consequences.

Central role for interleukin-4 in regulating nitric oxide-mediated inhibition of T-cell proliferation and gamma interferon production in schistosomiasis.

Schistosoma mansoni-infected wild-type (WT) mice develop a Th2 response and chronic disease. In contrast, infected interleukin-4 double-deficient (IL-4(-/-)) mice develop a Th1-like response and an acute, lethal syndrome. Disease severity in these animals correlates with excessive and prolonged production of nitric oxide (NO) associated with enhanced antigen-driven gamma interferon (IFN-gamma) production in the absence of IL-4. Strikingly, splenic lymphocytes from infected IL-4(-/-) mice failed to proliferate as well as those from infected WT mice following stimulation in vitro with antigen or anti-CD3 antibody. Contrary to antigen-driven IFN-gamma responses, anti-CD3 antibody stimulation of splenocytes resulted in significantly less IFN-gamma being produced by CD8 cells from infected IL-4(-/-) mice than by those from infected WT mice or normal mice. NO is largely responsible for the impaired T-cell functions in infected IL-4(-/-) mice, as inhibition of iNOS significantly enhanced proliferation and IFN-gamma production.