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The COVID-19 pandemic exposed mothers to stress and social isolation during the pre- and post-natal periods. The deleterious effects of stress on both pregnant women and their infants are well documented, with research suggesting that effects are exacerbated by reduced social support. In this brief report, we summarize evidence linking stress and social isolation to negative outcomes for mothers and infants and present a conceptual model featuring inflammation as a driving mechanism. There is strong evidence that the coronavirus pandemic will affect mothers and infants through immune pathways that, in previous research, have been shown to link stress and social isolation during the pre- and post-natal periods with deficits in maternal mental health and infant well-being and development across developmental stages. We close with recommendations for novel research, policy changes, and integrated clinical care that can address these biological threats to infants and mothers while leveraging the anti-inflammatory effects of social support.

Tick-borne diseases (TBDs) are bacterial, viral, and parasitic diseases transmitted by ticks. Viral TBDs have increased in prevalence over the last decade with many new pathogenic viruses being discovered. Doxycycline is often empirically prescribed by clinicians to treat symptomatic patients following tick bites due to suspicions of bacterial TBDs such as Rocky Mountain spotted fever, anaplasmosis, and ehrlichiosis. However, viral TBDs are included in the differential diagnosis if patients do not clinically improve following antibiotic therapy. Several viral TBDs present with dermatological manifestations. Recognizing the differences in clinical presentations of TBDs, particularly of newly emerging viral TBDs in the United States, can help physicians identify the viral TBD, and possibly rule out viral illnesses with different clinical presentations. Therefore, this review discusses clinical manifestations, with an emphasis on dermatologic manifestations of Heartland Virus, Bourbon Virus, Powassan Virus, Deer Tick Virus and Colorado Tick Fever Virus. Key points Viral tick-borne diseases have increased in prevalence over the last decade and often have similar clinical manifestations to other tick-borne diseases, including bacterial infections. Here, we review the dermatologic manifestations of Heartland Virus (HRTV), Bourbon Virus (BRBV), Powassan Virus (POWV), Deer Tick Virus (DTV) and Colorado Tick Fever Virus (CTFV) that are important for clinicians.

Colorado tick fever virus (CTFV) is an emerging Coltivirus belonging to the Reoviridae family and Spinareoviridae subfamily which can cause severe disease in humans. Several strains of CTFV have been previously described in the literature, including S6‐14‐03 (CTFV‐Ca), and the coltivirus‐type species, CTFV‐Florio. Following recent full genome sequencing, CTFV‐Ca is proposed to be a unique species within the Coltivirus genus rather than a serotype of CTFV‐Florio. CTFV‐Ca is closely related to human pathogenic coltiviruses, suggesting characterization is necessary to assess its pathogenic potential. We compared the ability of CTFV‐Florio and CTFV‐Ca to infect and proliferate within human dermal microvascular endothelial cells (HMEC‐1s) and detailed the potential immune responses during infection. Our results indicate that, like CTFV‐Florio, CTFV‐Ca is capable of infecting and proliferating within human endothelial cells (ECs). However, CTFV‐Ca is less efficient than CTFV‐Florio in our assays. Using RT‐qPCR gene arrays, we identified 41 genes that are significantly upregulated (> 2‐fold) upon infection including various proinflammatory cytokines and chemokines. Among the differentially upregulated genes, CTFV‐Florio typically induced a stronger response including on each occasion where significant differences were observed between the viruses. We also found both CTFV‐Florio and CTFV‐Ca capable of inducing proinflammatory responses at posttranslational levels as evidenced by significantly increased secretions of IFN‐β, IL‐6, IL‐8, and MCP‐1. Finally, we observed both increased EC permeability and death during CTFV‐Florio and CTFV‐Ca infection. These data describe for the first time a prospective antiviral response of human ECs to CTFV‐Ca infection and suggest that CTFV‐Ca can infect and stimulate potent antiviral and proinflammatory responses similar to the pathogenic Coltivirus‐type species, CTFV‐Florio.

We recently reported that the in vitro and in vivo survivals of Rickettsia australis are Atg5 -dependent, in association with an inhibited level of anti-rickettsial cytokine, IL-1β. In the present study, we sought to investigate how R. australis interacts with host innate immunity via an Atg5 -dependent autophagic response. We found that the serum levels of IFN-γ and G-CSF in R. australis -infected Atg5 flox/flox Lyz- Cre mice were significantly less compared to Atg5 flox/flox mice, accompanied by significantly lower rickettsial loads in tissues with inflammatory cellular infiltrations including neutrophils. R. australis infection differentially regulated a significant number of genes in bone marrow-derived macrophages (BMMs) in an Atg5 -depdent fashion as determined by RNA sequencing and Ingenuity Pathway Analysis, including genes in the molecular networks of IL-1 family cytokines and PI3K-Akt-mTOR. The secretion levels of inflammatory cytokines, such as IL-1α, IL-18, TNF-α, and IL-6, by R. australis- infected Atg5 flox/flox Lyz- Cre BMMs were significantly greater compared to infected Atg5 flox/flox BMMs. Interestingly , R. australis significantly increased the levels of phosphorylated mTOR and P70S6K at a time when the autophagic response is induced. Rapamycin treatment nearly abolished the phosphorylated mTOR and P70S6K but did not promote significant autophagic flux during R. australis infection. These results highlight that R. australis modulates an Atg5 -dependent autophagic response, which is not sensitive to regulation by mTORC1 signaling in macrophages. Overall, we demonstrate that R. australis counteracts host innate immunity including IL-1β-dependent inflammatory response to support the bacterial survival via an mTORC1-resistant autophagic response in macrophages.

Rickettsiae actively escape from vacuoles and replicate free in the cytoplasm of host cells, where inflammasomes survey the invading pathogens. In the present study, we investigated the interactions of Rickettsia australis with the inflammasome in both mouse and human macrophages. R. australis induced a significant level of IL-1β secretion by human macrophages, which was significantly reduced upon treatment with an inhibitor of caspase-1 compared to untreated controls, suggesting caspase-1-dependent inflammasome activation. Rickettsia induced significant secretion of IL-1β and IL-18 in vitro by infected mouse bone marrow-derived macrophages (BMMs) as early as 8-12 h post infection (p.i.) in a dose-dependent manner. Secretion of these cytokines was accompanied by cleavage of caspase-1 and was completely abrogated in BMMs deficient in caspase-1/caspase-11 or apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), suggesting that R. australis activate the ASC-dependent inflammasome. Interestingly, in response to the same quantity of rickettsiae, NLRP3-/- BMMs significantly reduced the secretion level of IL-1β compared to wild type (WT) controls, suggesting that NLRP3 inflammasome contributes to cytosolic recognition of R. australis in vitro. Rickettsial load in spleen, but not liver and lung, of R. australis-infected NLRP3-/- mice was significantly greater compared to WT mice. These data suggest that NLRP3 inflammasome plays a role in host control of bacteria in vivo in a tissue-specific manner. Taken together, our data, for the first time, illustrate the activation of ASC-dependent inflammasome by R. australis in macrophages in which NLRP3 is involved.

Rickettsiae primarily target microvascular endothelial cells. However, it remains elusive how endothelial cell responses to rickettsiae play a role in the pathogenesis of rickettsial diseases. In the present study, we employed two rickettsial species with high sequence homology but differing virulence to investigate the pathological endothelial cell responses. Rickettsia massiliae is a newly documented human pathogen that causes a mild spotted fever rickettsiosis. The \"Israeli spotted fever\" strain of R. conorii (ISF) causes severe disease with a mortality rate up to 30% in hospitalized patients. At 48 hours post infection (HPI), R. conorii (ISF) induced a significant elevation of IL-8 and IL-6 while R. massiliae induced a statistically significant elevated amount of MCP-1 at both transcriptional and protein synthesis levels. Strikingly, R. conorii (ISF), but not R. massiliae, caused a significant level of cell death or injury in HMEC-1 cells at 72 HPI, demonstrated by live-dead cell staining, annexin V staining and lactate dehydrogenase release. Monolayers of endothelial cells infected with R. conorii (ISF) showed a statistically significant decrease in electrical resistance across the monolayer compared to both R. massiliae-infected and uninfected cells at 72 HPI, suggesting increased endothelial permeability. Interestingly, pharmacological inhibitors of caspase-1 significantly reduced the release of lactate dehydrogenase by R. conorii (ISF)-infected HMEC-1 cells, which suggests the role of caspase-1 in mediating the death of endothelial cells. Taken together, our data illustrated that a distinct proinflammatory cytokine profile and endothelial dysfunction, as evidenced by endothelial cell death/injury and increased permeability, are associated with the severity of rickettsial diseases.

Older horses and those prone to obesity may be at a higher risk for inflammation than younger and leaner counterparts. Previous research indicated a postprandial elevation in plasma concentrations of interleukin-1β (IL-1β), a pro-inflammatory cytokine, after consuming 1.2 g of non-structural carbohydrates/kilogram of body weight. However, these studies utilized horses of mixed age and body condition. The current study evaluated post-prandial IL-1β concentrations in horses specifically comparing lean to over-conditioned and middle aged to older. Our results suggest that at least two weeks of daily consumption of a high non-structural carbohydrate diet is required to induce a post-prandial increase in IL-1β concentrations in younger and leaner horses. In opposition to this, older and over-conditioned horses experience plasma increased on the first day of feeding and thereafter. Feeding management practices of older and over-conditioned individuals should emphasize lower non-structural carbohydrate intakes and further research should elucidate mechanisms of IL-1β activation.

Manipulation of host cell death is an important determinant of the outcome of an infection. Here, we investigate whether Rickettsia rickettsii-infected host endothelial cells resist the effects of staurosporine, a potent inducer of apoptosis, and we explore the mechanisms underlying the anti-apoptotic effect of infection. Human microvascular endothelial cells infected with R. rickettsii for 24 or 48 h were challenged with staurosporine. The extent of apoptosis was evaluated with flow cytometry. mRNA and protein expression levels were determined by use of microarray or polymerase chain reaction and immunoblotting, respectively. Staurosporine-induced apoptosis in endothelial cells infected for 24 and 48 h was significantly reduced, compared with simultaneously treated uninfected cells. A microarray of human genes involved in apoptosis and polymerase chain reaction analyses revealed increased steady-state mRNA expression of cIAP2 (a member of the inhibitor-of-apoptosis family of proteins) at 24 h after infection. The levels of cIAP2 protein (+/-SD) in infected cells were 3.5 +/- 1.7 -fold and 2.3 +/- 1.2 -fold higher than that in uninfected control cells at 24 and 48 h after infection. Nucleofection of human-specific cIAP2-targeted siRNA resulted in inhibition of protein expression by > or = 50% but had no effect on infection-induced protection against apoptosis. R. rickettsii-induced expression of cIAP2 in host endothelial cells is likely not a major contributor to protection against staurosporine-induced cell death.

BackgroundManipulation of host cell death is an important determinant of the outcome of an infection. Here, we investigate whether Rickettsia rickettsii–infected host endothelial cells resist the effects of staurosporine, a potent inducer of apoptosis, and we explore the mechanisms underlying the anti-apoptotic effect of infection MethodsHuman microvascular endothelial cells infected with R. rickettsii for 24 or 48 h were challenged with staurosporine. The extent of apoptosis was evaluated with flow cytometry. mRNA and protein expression levels were determined by use of microarray or polymerase chain reaction and immunoblotting, respectively ResultsStaurosporine-induced apoptosis in endothelial cells infected for 24 and 48 h was significantly reduced, compared with simultaneously treated uninfected cells. A microarray of human genes involved in apoptosis and polymerase chain reaction analyses revealed increased steady-state mRNA expression of cIAP2 (a member of the inhibitor-of-apoptosis family of proteins) at 24 h after infection. The levels of cIAP2 protein (±SD) in infected cells were 3.5±1.7–fold and 2.3±1.2–fold higher than that in uninfected control cells at 24 and 48 h after infection. Nucleofection of human-specific cIAP2-targeted siRNA resulted in inhibition of protein expression by ⩾50% but had no effect on infection-induced protection against apoptosis Conclusions R. rickettsii–induced expression of cIAP2 in host endothelial cells is likely not a major contributor to protection against staurosporine-induced cell death

Cases of Ixodes scapularis (Blacklegged Tick or Deer Tick) are known to infest a variety of lizard species including Scincella lateralis (Ground Skink). We report the finding of 1 Ground Skink with an attached immature tick, later identified as an engorged Blacklegged Tick nymph, in a population with a low rate of tick infestation. Of the 151 Ground Skinks we collected at the Piney Woods Environmental Laboratory, only 1 was parasitized by any tick species. We extracted whole-body tick DNA and tested for various bacterial pathogens, including Anaplasma phagocytophilum, Ehrlichia spp., Borrelia spp., and Rickettsia spp. PCR tests for these pathogens were negative except for Rickettsia spp. Within our sampling region of Walker County, TX, in the East Texas Piney Woods, we estimated the infestation prevalence of Blacklegged Ticks utilizing Ground Skinks as a host at 0.66%, much lower than previous estimations in Oklahoma.