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Staphylococcus aureus (S. aureus) is an opportunistic pathogen causing diseases ranging from mild skin infections to life threatening conditions, including endocarditis, pneumonia, and sepsis. To identify host genes modulating this host-pathogen interaction, we infected 25 Collaborative Cross (CC) mouse strains with methicillin-resistant S. aureus (MRSA) and monitored disease progression for seven days using a surgically implanted telemetry system. CC strains varied widely in their response to intravenous MRSA infection. We identified eight 'susceptible' CC strains with high bacterial load, tissue damage, and reduced survival. Among the surviving strains, six with minimal colonization were classified as 'resistant', while the remaining six tolerated higher organ colonization ('tolerant'). The kidney was the most heavily colonized organ, but liver, spleen and lung colonization were better correlated with reduced survival. Resistant strains had higher pre-infection circulating neutrophils and lower post-infection tissue damage compared to susceptible and tolerant strains. We identified four CC strains with sexual dimorphism: all females survived the study period while all males met our euthanasia criteria earlier. In these CC strains, males had more baseline circulating monocytes and red blood cells. We identified several CC strains that may be useful as new models for endocarditis, myocarditis, pneumonia, and resistance to MRSA infection. Quantitative Trait Locus (QTL) analysis identified two significant loci, on Chromosomes 18 and 3, involved in early susceptibility and late survival after infection. We prioritized Npc1 and Ifi44l genes as the strongest candidates influencing survival using variant analysis and mRNA expression data from kidneys within these intervals.

According to the 2020 U.S. Census more than 60% of the U.S. population lives in towns with fewer than 50,000 residents, yet this is not in proportion with the research and public data surrounding policing, which focus on large and dense urban areas. One reason for this disparity is that studying small-town police departments presents unique obstacles. We present some of the challenges that we have encountered in studying small-town police activity such as data availability, quality, and identifiability, and our solutions to these challenges using computational tools. Finally, we give our recommendations in getting involved in this space based on our efforts to-date.

Abstract Given an infected host, estimating the time that has elapsed since initial exposure to the pathogen is an important problem in public health. In this paper we use longitudinal gene expression data from human challenge studies of viral respiratory illnesses for building predictive models to estimate the time elapsed since onset of respiratory infection. We apply sparsity driven machine learning to this time-stamped gene expression data to model the time of exposure by a pathogen and subsequent infection accompanied by the onset of the host immune response. These predictive models exploit the fact that the host gene expression profile evolves in time and its characteristic temporal signature can be effectively modeled using a small number of features. Predicting the time of exposure to infection to be in first 48 h after exposure produces BSR in the range of 80–90% on sequestered test data. A variety of machine learning experiments provide evidence that models developed on one virus can be used to predict exposure time for other viruses, e.g., H1N1, H3N2, and HRV. The interferon $$\alpha /\beta $$ α / β signaling pathway appears to play a central role in keeping time from onset of infection. Successful prediction of the time of exposure to a pathogen has potential ramifications for patient treatment and contact tracing.

ABSTRACT Understanding the molecular mechanisms underlying resistance and tolerance to pathogen infection may present the opportunity to develop novel interventions. Resistance is the absence of clinical disease with a low pathogen burden, while tolerance is minimal clinical disease with a high pathogen burden. Salmonella is a worldwide health concern. We studied 18 strains of collaborative cross mice that survive acute Salmonella Typhimurium (STm) infections. We infected these strains orally and monitored them for 3 weeks. Five strains cleared STm (resistant), six strains maintained a bacterial load and survived (tolerant), while seven strains survived >7 days but succumbed to infection within the study period and were called “delayed susceptible.” Tolerant strains were colonized in the Peyer’s patches, mesenteric lymph node, spleen, and liver, while resistant strains had significantly reduced bacterial colonization. Tolerant strains had lower preinfection core body temperatures and had disrupted circadian patterns of body temperature postinfection sooner than other strains. Tolerant strains had higher circulating total white blood cells than resistant strains, driven by increased numbers of neutrophils. Tolerant strains had more severe tissue damage and higher circulating levels of monocyte chemoattractant protein 1 (MCP-1) and interferon gamma (IFN-γ), but lower levels of epithelial neutrophil-activating protein 78 (ENA-78) than resistant strains. Quantitative trait locus (QTL) analysis revealed one significant association and six suggestive associations. Gene expression analysis identified 22 genes that are differentially regulated in tolerant versus resistant animals that overlapped these QTLs. Fibrinogen genes (Fga, Fgb, and Fgg) were found across the QTL, RNA, and top canonical pathways, making them the best candidate genes for differentiating tolerance and resistance. IMPORTANCE To survive a bacterial infection, an infected host can display resistance or tolerance. Resistance is indicated by a decrease in pathogen load, while for tolerance a high pathogen load is accompanied by minimal disease. We infected genetically diverse mice with Salmonella Typhimurium for 21 days and discovered new phenotypes for disease outcome (delayed susceptible, tolerant, and resistant). Tolerant strains showed the lowest preinfection core body temperatures and the most rapid disruption in circadian patterns of body temperature postinfection. Tolerant strains had higher circulating neutrophils and higher circulating levels of MCP-1 and IFN-γ, but lower levels of ENA-78 than did resistant strains, in addition to more severe tissue damage. QTL analysis revealed multiple associated regions, and gene expression analysis identified 22 genes that are differentially regulated in tolerant versus resistant animals in these regions. Fibrinogen genes (Fga, Fgb, and Fgg) were found across the QTL, RNA, and the top canonical pathways, suggesting a role in tolerance.

We present a sparsity-promoting RBF algorithm for time-series prediction. We use a time-delayed embedding framework and model the function from the embedding space to predict the next point in the time series. We explore the standard benchmark data set generated by the Mackey–Glass chaotic dynamical system. We also consider a model of temperature telemetry associated with the mouse model immune response to infection. We see that significantly reduced models can be obtained by solving the penalized RBF fitting problem.

Salmonella infections typically cause self-limiting gastroenteritis, but in some individuals these bacteria can spread systemically and cause disseminated disease. Salmonella Typhimurium (STm), which causes severe systemic disease in most inbred mice, has been used as a model for disseminated disease. To screen for new infection phenotypes across a range of host genetics, we orally infected 32 Collaborative Cross (CC) mouse strains with STm and monitored their disease progression for seven days by telemetry. Our data revealed a broad range of phenotypes across CC strains in many parameters including survival, bacterial colonization, tissue damage, complete blood counts (CBC), and serum cytokines. Eighteen CC strains survived to day 7, while fourteen susceptible strains succumbed to infection before day 7. Several CC strains had sex differences in survival and colonization. Surviving strains had lower pre-infection baseline temperatures and were less active during their daily active period. Core body temperature disruptions were detected earlier after STm infection than activity disruptions, making temperature a better detector of illness. All CC strains had STm in spleen and liver, but susceptible strains were more highly colonized. Tissue damage was weakly negatively correlated to survival. We identified loci associated with survival on Chromosomes (Chr) 1, 2, 4, 7. Polymorphisms in Ncf2 and Slc11a1, known to reduce survival in mice after STm infections, are located in the Chr 1 interval, and the Chr 7 association overlaps with a previously identified QTL peak called Ses2. We identified two new genetic regions on Chr 2 and 4 associated with susceptibility to STm infection. Our data reveal the diversity of responses to STm infection across a range of host genetics and identified new candidate regions for survival of STm infection.