TY - JOUR
T1 - Neuroinflammation associated with scrub typhus and spotted fever group rickettsioses
AU - Fisher, James
AU - Card, Galen
AU - Soong, Lynn
N1 - Funding Information:
This work was supported generously by National Institute of Allergy and Infectious Diseases grants (grant numbers AI 132674, AI 126343, and T32 AI 007526 to LS, https://www.niaid.nih.gov), T32 Emerging and Tropical Infectious Diseases Predoctoral Fellowship (to JF), UTMB Institute for Human Infections and Immunity Pilot Grant (LS, https://www.utmb.edu/ihii), UTMB John W. McLaughlin Predoctoral Fellowship (to GC), and DoD grant (HDTRA1-19-1-0043 to LS, www. defense.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2020 Fisher et al.
PY - 2020/10
Y1 - 2020/10
N2 - Scrub typhus and spotted fever rickettsioses (SFR) are understudied, vector-borne diseases of global significance. Over 1 billion individuals are at risk for scrub typhus alone in an endemic region, spanning across eastern and southern Asia to Northern Australia. While highly treatable, diagnostic challenges make timely antibiotic intervention difficult for these diseases. Delayed therapy may lead to severe outcomes affecting multiple organs, including the central nervous system (CNS), where infection and associated neuroinflammation may be lethal or lead to lasting sequelae. Meningitis and encephalitis are prevalent in both scrub typhus and SFR. Additionally, case reports detailing focal neurological deficits have come to light, with attention to both acute and chronic sequelae of infection. Despite the increasing number of clinical reports outlining neurologic consequences of these diseases, relatively little research has examined underlying mechanisms of neuroinflammation. Animal models of scrub typhus have identified cerebral T-cell infiltration and vascular damage associated with endothelial infection and neuropathogenesis. Differential gene expression analysis of brain tissues during murine scrub typhus have revealed selective increases in CXCR3 ligands, proinflammatory and type-1 cytokines and chemokines, and cytotoxicity molecules, as well as alterations in the complement pathway. In SFR, microglial expansion and macrophage infiltration contribute to neurological disease progression. This narrative Review highlights clinical neurologic features of scrub typhus and SFR and evaluates our current understanding of basic research into neuroinflammation for both diseases in animal models. Further investigation into key mediators of neuropathogenesis may yield prognostic markers and treatment regimens for severe patients.
AB - Scrub typhus and spotted fever rickettsioses (SFR) are understudied, vector-borne diseases of global significance. Over 1 billion individuals are at risk for scrub typhus alone in an endemic region, spanning across eastern and southern Asia to Northern Australia. While highly treatable, diagnostic challenges make timely antibiotic intervention difficult for these diseases. Delayed therapy may lead to severe outcomes affecting multiple organs, including the central nervous system (CNS), where infection and associated neuroinflammation may be lethal or lead to lasting sequelae. Meningitis and encephalitis are prevalent in both scrub typhus and SFR. Additionally, case reports detailing focal neurological deficits have come to light, with attention to both acute and chronic sequelae of infection. Despite the increasing number of clinical reports outlining neurologic consequences of these diseases, relatively little research has examined underlying mechanisms of neuroinflammation. Animal models of scrub typhus have identified cerebral T-cell infiltration and vascular damage associated with endothelial infection and neuropathogenesis. Differential gene expression analysis of brain tissues during murine scrub typhus have revealed selective increases in CXCR3 ligands, proinflammatory and type-1 cytokines and chemokines, and cytotoxicity molecules, as well as alterations in the complement pathway. In SFR, microglial expansion and macrophage infiltration contribute to neurological disease progression. This narrative Review highlights clinical neurologic features of scrub typhus and SFR and evaluates our current understanding of basic research into neuroinflammation for both diseases in animal models. Further investigation into key mediators of neuropathogenesis may yield prognostic markers and treatment regimens for severe patients.
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U2 - 10.1371/journal.pntd.0008675
DO - 10.1371/journal.pntd.0008675
M3 - Review article
C2 - 33091013
AN - SCOPUS:85094155270
VL - 14
SP - 1
EP - 15
JO - PLoS Neglected Tropical Diseases
JF - PLoS Neglected Tropical Diseases
SN - 1935-2727
IS - 10
M1 - e0008675
ER -