DISPERSION OF AEROSOLIZED BACTERIA FROM ASIAN ELEPHANTS (ELEPHAS MAXIMUS).

Transmission of tuberculosis typically requires close and prolonged contact with an infected individual. However, several cases of transmission between elephants and from elephants to humans or other animals without direct contact or over long distances have been reported. Elephants have been shown to be capable of producing aerosolized bacterial droplets, suggesting a possible route of transmission that is magnified by the size and force of the elephant respiratory tract. To investigate the dispersion and viability of aerosolized bacteria generated from the elephant respiratory tract, a pre-existing model with a proxy organism was used. A six-stage Andersen sampler was used to detect the proxy organism, a commensal elephant respiratory bacterium, at different locations around an elephant barn at a zoo. The amount of proxy organism detected at various time points and distances from the elephants indicates they are capable of dispersing viable bacterial aerosols further than humans can. The concentration of these aerosols is dependent on proximity to the elephants and does not remain at a high level for prolonged periods of time. These findings support the model of aerosol-mediated transmission of bacteria from elephants and can be used to improve disease management practices and prevent the spread of pathogens from elephants in zoos and other facilities.

Thrombin Signaling Promotes Pancreatic Adenocarcinoma through PAR-1-Dependent Immune Evasion.

Pancreatic ductal adenocarcinoma (PDAC) is associated with robust activity of the coagulation system. To determine mechanisms by which clotting factors influence PDAC tumor progression, we generated and characterized C57Bl/6-derived KPC (KRasG12D, TRP53R172H ) cell lines. Tissue factor (TF) and protease-activated receptor-1 (PAR-1) were highly expressed in primary KPC pancreatic lesions and KPC cell lines similar to expression profiles observed in biopsies of patients with PDAC. In allograft studies, tumor growth and metastatic potential were significantly diminished by depletion of TF or Par-1 in cancer cells or by genetic or pharmacologic reduction of the coagulation zymogen prothrombin in mice. Notably, PAR-1-deleted KPC cells (KPC-Par-1KO) failed to generate sizable tumors, a phenotype completely rescued by restoration of Par-1 expression. Expression profiling of KPC and KPC-Par-1KO cells indicated that thrombin-PAR-1 signaling significantly altered immune regulation pathways. Accordingly, KPC-Par-1KO cells failed to form tumors in immune-competent mice but displayed robust tumor growth comparable to that observed with control KPC cells in immune-compromised NSG mice. Immune cell depletion studies indicated that CD8 T cells, but not CD4 cells or natural killer cells, mediated elimination of KPC-Par-1KO tumor cells in C57Bl/6 mice. These results demonstrate that PDAC is driven by activation of the coagulation system through tumor cell-derived TF, circulating prothrombin, and tumor cell-derived PAR-1 and further indicate that one key mechanism of thrombin/PAR-1-mediated tumor growth is suppression of antitumor immunity in the tumor microenvironment. SIGNIFICANCE: The tissue factor-thrombin-PAR-1 signaling axis in tumor cells promotes PDAC growth and disease progression with one key mechanism being suppression of antitumor immunity in the microenvironment.