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1. An Infection-Tolerant Mammalian Reservoir for Several Zoonotic Agents Broadly Counters the Inflammatory Effects of Endotoxin

   https://doi.org/10.1128/mBio.00588-21  

   Balderrama-Gutierrez, Gabriela; Milovic, Ana; Cook, Vanessa J.; Islam, M. Nurul; Zhang, Youwen; Kiaris, Hippokratis; Belisle, John T.; Mortazavi, Ali; Barbour, Alan G. (April 2021, mBio)

   Miller, Samuel I. (Ed.)

   ABSTRACT Animals that are competent reservoirs of zoonotic pathogens commonly suffer little morbidity from the infections. To investigate mechanisms of this tolerance of infection, we used single-dose lipopolysaccharide (LPS) as an experimental model of inflammation and compared the responses of two rodents: Peromyscus leucopus , the white-footed deermouse and reservoir for the agents of Lyme disease and other zoonoses, and the house mouse Mus musculus . Four hours after injection with LPS or saline, blood, spleen, and liver samples were collected and subjected to transcriptome sequencing (RNA-seq), metabolomics, and specific reverse transcriptase quantitative PCR (RT-qPCR). Differential expression analysis was at the gene, pathway, and network levels. LPS-treated deermice showed signs of sickness similar to those of exposed mice and had similar increases in corticosterone levels and expression of interleukin 6 (IL-6), tumor necrosis factor, IL-1β, and C-reactive protein. By network analysis, the M. musculus response to LPS was characterized as cytokine associated, while the P. leucopus response was dominated by neutrophil activity terms. In addition, dichotomies in the expression levels of arginase 1 and nitric oxide synthase 2 and of IL-10 and IL-12 were consistent with type M1 macrophage responses in mice and type M2 responses in deermice. Analysis of metabolites in plasma and RNA in organs revealed species differences in tryptophan metabolism. Two genes in particular signified the different phenotypes of deermice and mice: the Slpi and Ibsp genes. Key RNA-seq findings for P. leucopus were replicated in older animals, in a systemic bacterial infection, and with cultivated fibroblasts. The findings indicate that P. leucopus possesses several adaptive traits to moderate inflammation in its balancing of infection resistance and tolerance. IMPORTANCE Animals that are natural carriers of pathogens that cause human diseases commonly manifest little or no sickness as a consequence of infection. Examples include the deermouse, Peromyscus leucopus , which is a reservoir for Lyme disease and several other disease agents in North America, and some types of bats, which are carriers of viruses with pathogenicity for humans. Mechanisms of this phenomenon of infection tolerance and entailed trade-off costs are poorly understood. Using a single injection of lipopolysaccharide (LPS) endotoxin as a proxy for infection, we found that deermice differed from the mouse ( Mus musculus ) in responses to LPS in several diverse pathways, including innate immunity, oxidative stress, and metabolism. Features distinguishing the deermice cumulatively would moderate downstream ill effects of LPS. Insights gained from the P. leucopus model in the laboratory have implications for studying infection tolerance in other important reservoir species, including bats and other types of wildlife. 

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2. Comparative transcriptome analysis of Peromyscus leucopus and C3H mice infected with the Lyme disease pathogen

   https://doi.org/10.3389/fcimb.2023.1115350  

   Gaber, Alhussien M.; Mandric, Igor; Nitirahardjo, Caroline; Piontkivska, Helen; Hillhouse, Andrew E.; Threadgill, David W.; Zelikovsky, Alex; Rogovskyy, Artem S. (April 2023, Frontiers in Cellular and Infection Microbiology)

   Lyme disease (LD), the most prevalent tick-borne disease of humans in the Northern Hemisphere, is caused by the spirochetal bacterium of Borreliella burgdorferi ( Bb ) sensu lato complex. In nature, Bb spirochetes are continuously transmitted between Ixodes ticks and mammalian or avian reservoir hosts. Peromyscus leucopus mice are considered the primary mammalian reservoir of Bb in the United States. Earlier studies demonstrated that experimentally infected P. leucopus mice do not develop disease. In contrast, C3H mice, a widely used laboratory strain of Mus musculus in the LD field, develop severe Lyme arthritis. To date, the exact tolerance mechanism of P. leucopus mice to Bb -induced infection remains unknown. To address this knowledge gap, the present study has compared spleen transcriptomes of P. leucopus and C3H/HeJ mice infected with Bb strain 297 with those of their respective uninfected controls. Overall, the data showed that the spleen transcriptome of Bb -infected P. leucopus mice was much more quiescent compared to that of the infected C3H mice. To date, the current investigation is one of the few that have examined the transcriptome response of natural reservoir hosts to Borreliella infection. Although the experimental design of this study significantly differed from those of two previous investigations, the collective results of the current and published studies have consistently demonstrated very limited transcriptomic responses of different reservoir hosts to the persistent infection of LD pathogens. Importance The bacterium Borreliella burgdorferi ( Bb ) causes Lyme disease, which is one of the emerging and highly debilitating human diseases in countries of the Northern Hemisphere. In nature, Bb spirochetes are maintained between hard ticks of Ixodes spp. and mammals or birds. In the United States, the white-footed mouse, Peromyscus leucopus , is one of the main Bb reservoirs. In contrast to humans and laboratory mice (e.g., C3H mice), white-footed mice rarely develop clinical signs (disease) despite being (persistently) infected with Bb . How the white-footed mouse tolerates Bb infection is the question that the present study has attempted to address. Comparisons of genetic responses between Bb -infected and uninfected mice demonstrated that, during a long-term Bb infection, C3H mice reacted much stronger, whereas P. leucopus mice were relatively unresponsive. 

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3. Hantavirus in rodents in the United States: Temporal and spatial trends and report of new hosts

   https://doi.org/10.1002/ecs2.70209  

   Astorga, Francisca; Alkishe, Abdelghafar; Paansri, Paanwaris; Mantilla, Gabriel; Escobar, Luis_E (March 2025, Ecosphere)

   Abstract In North America, the rodent‐borne hantavirus pulmonary syndrome is predominantly caused by the Sin Nombre virus, typically associated with the deer mousePeromyscus maniculatus. Utilizing data from the National Ecological Observatory Network (NEON) hantavirus program, we assessed factors that may influence the spatial and temporal distribution of hantavirus in rodent populations across the United States. Between 2014 and 2019, the NEON hantavirus program conducted 104,379 small mammal captures and collected 14,004 blood samples from 49 species at 45 field sites. Our study identified 296 seropositive samples across 15 rodent species, including 8Peromyscusspecies. We describe six new species with hantavirus seropositive samples not previously reported as hantavirus hosts. The highest number of seropositive samples was obtained fromPe. maniculatus(n = 116; 2.9% seroprevalence), followed byPeromyscus leucopus(n = 96; 2.8%) andMicrotus pennsylvanicus(n = 33; 4.2%). Hantavirus seroprevalence showed an uneven spatial distribution, with the highest seroprevalence found in Virginia (7.8%, 99 seropositive samples), Colorado (5.7%,n = 37), and Texas (4.8%,n = 19). Hantavirus seropositive samples were obtained from 32 sites, 10 of which presented seropositive samples in species other thanPe. maniculatusorPe. leucopus. Seroprevalence was inconsistent across years but showed intra‐annual bimodal trends, and inPe. maniculatusandPe. leucopus, the number of captures correlated with seroprevalence in the following months. Seroprevalence was higher in adult males, with only one seropositive sample obtained from a juvenilePeromyscus truei. Higher body mass, presence of scrotal testes, and nonpregnant status were associated with higher seropositivity. The NEON dataset, derived from a multiyear and structured surveillance system, revealed the extensive distribution of hantavirus across broad taxonomic and environmental ranges. Future research should consider winter season surveillance and continued analyses of stored samples for a comprehensive spatiotemporal study of hantavirus circulation in wildlife. Global changes are expected to affect the dynamics of rodent populations by affecting their availability of resources and demography and, consequently, may modify transmission rates of rodent‐borne zoonotic pathogens such as hantavirus. This study can be considered a baseline to assess hantavirus patterns across host taxa, geographies, and seasons in the United States. 

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4. In the Lyme light: individual trait determinants of Borrelia burgdorferi infection in Peromyscus mice

   https://doi.org/10.1093/jmammal/gyad108  

   Yen, Ivy; Gardner, Allison; Mortelliti, Alessio (November 2023, Journal of Mammalogy)

   Wang, Guiming (Ed.)

   Abstract Disease ecologists commonly use abiotic factors (e.g. temperature and moisture) or measures of biodiversity (e.g. species richness) to predict Lyme disease transmission patterns, but variance in infection probability among individuals within a population is poorly understood. Most studies assume intraspecific consistency, but recent evidence suggests that individual traits, such as animal personality, may drive differences in encounter rates with infected vectors and pathogen transmission probabilities through differential space use and microhabitat selection, leading to intraspecific variation in infection probability. In addition, because vectors and hosts are nonrandomly distributed across a landscape, land-use changes that modify key habitat features—such as forest management practices—may substantially alter associations between individual traits and infection probability. To address these gaps in our knowledge, we used a large-scale capture–mark–recapture study targeting Peromyscus mice in Maine, United States, to test whether personality drives probability of Borrelia burgdorferi infection in hosts within managed forest compartments with different silvicultural treatments. Specifically, we tested effects of individual phenotypic traits (physical and behavioral) and environmental traits (microhabitat and forest type) on infection probability within 2 species: P. leucopus and P. maniculatus. We found evidence that boldness negatively influences infection probability in P. maniculatus, and that body mass positively influences infection probability in both species. We found no effect of mouse density, microhabitat, or forest type in our analyses. These results suggest that personalities vary in their functional contributions to the natural cycle of B. burgdorferi, and that broader integration of behavioral diversity in disease ecology studies may aid in identifying key transmission zones for this rapidly expanding vector-borne zoonosis. 

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5. Ecology of Ixodes pacificus Ticks and Associated Pathogens in the Western United States

   https://doi.org/10.3390/pathogens11010089  

   McVicar, Molly; Rivera, Isabella; Reyes, Jeremiah B.; Gulia-Nuss, Monika (January 2022, Pathogens)

   Lyme disease is the most important vector-borne disease in the United States and is increasing in incidence and geographic range. In the Pacific west, the western black-legged tick, Ixodes pacificus Cooley and Kohls, 1943 is an important vector of the causative agent of Lyme disease, the spirochete, Borrelia burgdorferi. Ixodes pacificus life cycle is expected to be more than a year long, and all three stages (larva, nymph, and adult) overlap in spring. The optimal habitat consists of forest cover, cooler temperatures, and annual precipitation in the range of 200–500 mm. Therefore, the coastal areas of California, Oregon, and Washington are well suited for these ticks. Immature stages commonly parasitize Western fence lizards (Sceloporus occidentalis) and gray squirrels (Sciurus griseus), while adults often feed on deer mice (Peromyscus maniculatus) and black-tailed deer (Odocoileus h. columbianus). Ixodes pacificus carry several pathogens of human significance, such as Borrelia burgdorferi, Bartonella, and Rickettsiales. These pathogens are maintained in the environment by many hosts, including small mammals, birds, livestock, and domestic animals. Although a great deal of work has been carried out on Ixodes ticks and the pathogens they transmit, understanding I. pacificus ecology outside California still lags. Additionally, the dynamic vector–host–pathogen system means that new factors will continue to arise and shift the epidemiological patterns within specific areas. Here, we review the ecology of I. pacificus and the pathogens this tick is known to carry to identify gaps in our knowledge. 

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