Dermatological manifestations of tick-borne viral infections found in the United States

Abstract 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

Vector Tick Transmission Model of Spotted Fever Rickettsiosis

Many aspects of rickettsial infections have been characterized, including pathogenic and immune pathways and mechanisms of rickettsial survival within the vertebrate host and tick vector. However, very few studies are focused on the complex pathogen–vector–host interactions during tick feeding. Therefore, our objective was to develop a tick transmission model of the spotted fever group of rickettsial infections to study the initial events in disease development. The most appropriate strain of mouse was identified for evaluation as a transmission model, and the course of infection, bacterial levels, histopathologic changes, and antibody response during tick transmission in mice infested with Amblyomma maculatum ticks carrying the emerging pathogen, Rickettia parkeri, were studied. Results showed distinct clinical signs in C3H/HeN mice infected intravenously, leading to selection of this mouse strain for tick transmission studies. Active infection of animals was observed after tick vector transmission. The bacteria disseminated systemically and spread to several organs at 24 hours after tick attachment, with peak bacterial load at day 6 after tick attachment. Skin, lung, and liver showed the greatest pathologic changes, with inflammatory cellular infiltration and necrosis. These findings indicate the feasibility of using murine infection with R. parkeri by A. maculatum tick transmission as a model to study different aspects of the spotted fever group of rickettsial disease establishment

Rickettsia massiliae and Rickettsia conorii Israeli Spotted Fever Strain Differentially Regulate Endothelial Cell Responses.

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

<i>R</i>. <i>conorii</i> (ISF) induced significant secretion of IL-8 and IL-6, while <i>R</i>. <i>massiliae</i> induced significant production of MCP-1 in infected HMEC-1 cells.

<p>The production levels of MCP-1 (A), IL-8 (B) and IL-6 (C) in the supernatant of <i>Rickettsia</i>-infected HMEC-1 cells was assessed by ELISA. Bar graphs indicate the average and standard error of three independent experiments. White bars represent uninfected cells, grey bars represent <i>R</i>. <i>massiliae</i>-infected cells, and <i>R</i>. <i>conorii</i> (ISF)—infected cells are represented by black bars. *, <i>p</i> < 0.05, ** n.s. = non-statistically significant.</p

<i>R</i>. <i>massiliae</i> and <i>R</i>. <i>conorii</i> (ISF) infection resulted in plaques in Vero cell monolayers and replicated efficiently in the human dermal microvascular cell line, HMEC-1 cells.

<p>(A) <i>R</i>. <i>massiliae</i> and <i>R</i>. <i>conorii</i> (ISF) were grown in Vero cells at 34°C for 5 and 7 days to quantify the number of plaques present as revealed by crystal violet staining (B). <i>R</i>. <i>massiliae</i> and <i>R</i>. <i>conorii</i> (ISF) were grown in HMEC-1 cells for times indicated. Data are representative of three independent experiments (A and B).</p

<i>R</i>. <i>conorii</i> (ISF), but not <i>R</i>. <i>massiliae</i>, induced cell death at 72 HPI in HMEC-1 cells: (A) Cells were infected at an MOI of 5 and stained with Live/Dead fixable dye for 30 minutes before fixation in paraformaldehyde.

<p>For flow cytometry experiments, ⩾10,000 cells were analyzed. (B) Annexin V staining of HMEC-1 cells following 72 hours of infection with <i>R</i>. <i>massiliae</i> or <i>R</i>. <i>conorii</i> (ISF). Cell counts were normalized to mode. (C) Lactate dehydrogenase (LDH) activity assay of monolayer supernatants demonstrating significantly increased levels of endothelial cell cytotoxicity after infection with <i>R</i>. <i>conorii</i> (ISF) for 72 hours. Bar graphs (A and C) indicate the average and standard error of three independent experiments. White bars represent uninfected cells, grey bars represent <i>R</i>. <i>massiliae</i>-infected cells, <i>R</i>. <i>conorii</i> (ISF)-infected cells are represented by black bars, and cells treated with staurosporine are represented by the checkered bar. *, <i>p</i> < 0.05.</p

Endothelial cell death induced by <i>R</i>. <i>conorii</i> (ISF) is partially dependent on caspase-1.

<p>Cells were treated with caspase-1 and caspase-4 inhibitors and then infected with <i>R</i>. <i>conorii</i> (ISF) for 72 hours. Fresh medium and caspase inhibitors were added daily, and the removed supernatant was used immediately for the LDH activity assay. The bar graph indicates the average and standard error of three independent experiments. *, <i>p</i> < 0.05, inh = inhibitor, Rc = <i>R</i>. <i>conorii</i> (ISF), casp = caspase.</p

Inflammatory and Environmental Contributions to Social Information Processing

It appears that social information processing is negatively affected by inflammation, but extant research is primarily experimental and comes from laboratory-based manipulations of inflammatory states. We aimed to examine interactions between inflammation, stressful life events, and positive memories of childhood relations with parents in relation to social information processing in 201 adults. We hypothesized that increased inflammation and stressful life events would be associated with greater hostile social information processing, but that positive memories of childhood relations with parents would moderate both relations. Results indicated that high IL-6 levels and stressful life events were significantly associated with direct and hostile social information processing. Positive memories of childhood relations with parents attenuated the link between stressful life events and social information processing. Findings suggest that both immune function and environmental stressors are related to social information processing and that positive memories of childhood relations exert some buffering effect

<i>R</i>. <i>conorii</i> (ISF), but not <i>R</i>. <i>massiliae</i>, increased endothelial cell monolayer permeability.

<p>(A) Representative ECIS graph demonstrating the loss of electrical resistance across an HMEC-1 monolayer in real-time. (B) Average resistance of endothelial cell monolayers after infection with rickettsiae for designated time points. Bar graphs (B) indicate the average and standard error of three independent experiments. White bars represent uninfected cells, grey bars represent <i>R</i>. <i>massiliae</i>-infected cells, and <i>R</i>. <i>conorii</i> (ISF)—infected cells are represented by black bars. *, <i>p</i> < 0.05.</p

Rickettsia australis Activates Inflammasome in Human and Murine 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