Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates

Trypanosoma cruzi, the agent of Chagas disease, probably infects tens of millions of people, primarily in Latin America, causing morbidity and mortality. The options for treatment and prevention of Chagas disease are limited and underutilized. Here we describe the discovery of a series of benzoxaborole compounds with nanomolar activity against extra- and intracellular stages of T. cruzi. Leveraging both ongoing drug discovery efforts in related kinetoplastids, and the exceptional models for rapid drug screening and optimization in T. cruzi, we have identified the prodrug AN15368 that is activated by parasite carboxypeptidases to yield a compound that targets the messenger RNA processing pathway in T. cruzi. AN15368 was found to be active in vitro and in vivo against a range of genetically distinct T. cruzi lineages and was uniformly curative in non-human primates (NHPs) with long-term naturally acquired infections. Treatment in NHPs also revealed no detectable acute toxicity or long-term health or reproductive impact. Thus, AN15368 is an extensively validated and apparently safe, clinically ready candidate with promising potential for prevention and treatment of Chagas disease

sj-pdf-2-vet-10.1177_03009858231203315 – Supplemental material for Analysis of cell populations in the normal rhesus macaque (Macaca mulatta) lower intestinal tract and diagnostic thresholds for chronic enterocolitis

Supplemental material, sj-pdf-2-vet-10.1177_03009858231203315 for Analysis of cell populations in the normal rhesus macaque (Macaca mulatta) lower intestinal tract and diagnostic thresholds for chronic enterocolitis by Rebecca L. Bacon, Loni Taylor, Stanton B. Gray and Carolyn L. Hodo in Veterinary Pathology</p

sj-xlsx-1-vet-10.1177_03009858231203315 – Supplemental material for Analysis of cell populations in the normal rhesus macaque (Macaca mulatta) lower intestinal tract and diagnostic thresholds for chronic enterocolitis

Supplemental material, sj-xlsx-1-vet-10.1177_03009858231203315 for Analysis of cell populations in the normal rhesus macaque (Macaca mulatta) lower intestinal tract and diagnostic thresholds for chronic enterocolitis by Rebecca L. Bacon, Loni Taylor, Stanton B. Gray and Carolyn L. Hodo in Veterinary Pathology</p

Lack of Trypanosoma cruzi Infection in Urban Roof Rats (Rattus rattus) at a Texas Facility Housing Naturally Infected Nonhuman Primates

The protozoan parasite Trypanosoma cruzi causes Chagas disease, uses kissing bugs as a vector, and is maintained in nature by a variety of wildlife reservoirs. Many natural cases of Chagas disease have been reported in NHP at facilities across the southern United States, where infected vectors and wildlife occur. Infection of NHP with T. cruzi can diminish their value as research models and lead to health problems and death. Identifying the modes of transmission and role of wildlife reservoirs in these facilities is therefore critical to guide interventions to reduce transmission. Here we investigated the role of roof rats (Rattus rattus), the most abundant nuisance species at a primate facility in San Antonio, in the maintenance and transmission of T. cruzi. The hearts and blood from the carcasses of the 145 rats collected underwent 2 independent PCR assays for detection of T. cruzi and other trypanosomes. The 145 hearts and 61 blood samples were all negative for T. cruzi. This population sample of 145 subjects would allow the detection of disease prevalence of 0.020 with a confidence level of 95%. The limited active vector surveillance efforts by our team combined with passive surveillance by facility personnel yielded no kissing bugs during the study period. Our results suggest that roof rats are unlikely to be important local reservoirs of T. cruzi at this facility. Further investigation of transmission dynamics across multiple years and more comprehensive vector surveillance is warranted

Repeated cross‐sectional study of Trypanosoma cruzi in shelter dogs in Texas, in the context of Dirofilaria immitis and tick‐borne pathogen prevalence

Background Vector‐borne diseases have an adverse impact on health of dogs, and infected dogs can be sentinels for human infection. Infection with Trypanosoma cruzi, an agent of Chagas disease, causes fatal heart disease in dogs across the southern United States but has been neglected from wide‐scale prevalence studies. Objectives To determine the prevalence of exposure to T. cruzi, Ehrlichia spp., Anaplasma spp., Borrelia burgdorferi, and infection with Dirofilaria immitis among dogs in shelters across Texas and to identify risk factors for T. cruzi seropositivity. Animals Six hundred and eight dogs. Methods This repeated cross‐sectional study was performed by collecting blood from ~30 dogs during each of the 3 visits to 7 shelters. We tested serum for antibodies to T. cruzi using 2 tests in series and for antibodies to Ehrlichia spp., Anaplasma spp., and B. burgdorferi and D. immitis antigen using the IDEXX SNAP 4DX Plus point‐of‐care test. DNA was extracted from blood clots and tested for T. cruzi DNA and strain type via quantitative polymerase chain reactions (qPCR). We used logistic regression to assess risk factors. Results One hundred ten (18.1%) of 608 dogs were seropositive for T. cruzi. Prevalence of exposure to the other vector‐borne agents was: Ehrlichia spp. 3.6%; Anaplasma spp. 6.9%; B. burgdorferi 0.2%; and D. immitis infection 16.0%. Six of 559 (1.1%) dogs were qPCR‐positive for T. cruzi. Conclusions and Clinical Importance T. cruzi seroprevalence was comparable to D. immitis prevalence and higher than seroprevalence of the tick‐borne pathogens. T. cruzi is an underrecognized health threat to dogs across Texas and possibly other southern states where triatomine vectors are endemic

Novel Poxvirus in Proliferative Lesions of Wild Rodents in East Central Texas, USA

Northern pygmy mice from 2 localities in East Central Texas, USA, had proliferative epidermal lesions on the tail and feet. Electron microscopy of lesion tissue revealed poxvirus. Phylogenetic analyses indicated the virus differed 35% from its closest relatives, the Chordopoxvirinae. Future research is needed to determine whether this virus could affect human health

Comparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair-deficient colorectal cancer.

Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029C<G, p.Tyr343Ter). Our study aimed to provide a detailed molecular characterization of rhesus CRC for cross-comparison with human MMRd CRC. We performed PCR-based MSI testing (n = 41), transcriptomics analysis (n = 35), reduced-representation bisulfite sequencing (RRBS) (n = 28), and MLH1 DNA methylation (n = 10) using next-generation sequencing (NGS) of rhesus CRC. Systems biology tools were used to perform gene set enrichment analysis (GSEA) for pathway discovery, consensus molecular subtyping (CMS), and somatic mutation profiling. Overall, the majority of rhesus tumors displayed high levels of MSI (MSI-H) and differential gene expression profiles that were consistent with known deregulated pathways in human CRC. DNA methylation analysis exposed differentially methylated patterns among MSI-H, MSI-L (MSI-low)/MSS (MS-stable) and LS tumors with MLH1 predominantly inactivated among sporadic MSI-H CRCs. The findings from this study support the use of rhesus macaques as an alternative animal model to mice to study carcinogenesis, develop immunotherapies and vaccines, and implement chemoprevention approaches relevant to sporadic MSI-H and LS CRC in humans