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CD8+ T cells provide immune protection against murine disseminated endotheliotropic Orientia tsutsugamushi infection.

Abstract Scrub typhus, caused by a Gram-negative obligately intracellular coccobacillus, Orientia tsutsugamushi, is a long neglected but important tropical disease. Orientia tsutsugamushi causes illness in one million people each year, and 1 billion people are at risk. Without appropriate diagnosis and treatment, the disease can cause severe multiorgan failure with a case fatality rate of 7-15%. The current gaps in knowledge of immunity include the unknown mechanisms of host immunity to O. tsutsugamushi. Using an intravenous (i.v.) disseminated infection mouse model, we observed that more CD8+ T cells than CD4+ T cells were present in the spleen of infected mice at 12 dpi. We also determined that Treg cells and the proportion of T cells producing IL-10 were significantly increased from 6 dpi, which correlated with the onset of illness, body weight loss, and increased bacterial loads. We further studied CD8-/-, MHC I-/- and wild type control (WT) C57BL/6J mice to determine the importance of CD8+ T cells and MHC I molecules. After infection with an ordinarily sub-lethal dose of O. tsutsugamushi, all CD8-/- and MHC I-/- mice were moribund between 12 and 15 dpi, whereas all WT mice survived. Bacterial loads in the lung, kidney, liver and spleen of CD8-/- and MHC I-/- mice were significantly greater than those in WT mice. Interferon-γ (IFN-γ) and granzyme B mRNA levels in the liver of CD8-/- and MHC I-/- mice were significantly greater than in WT mice. In addition, more severe histopathologic lesions were observed in CD8-/- mice. Finally, adoptive transfer confirmed a major role of immune CD8+ T cells as well as a less effective contribution by immune CD8 T cell-depleted splenocytes in protection against O. tsutsugamushi infection. These studies demonstrated the critical importance of CD8+ T cells in the host immune response during O. tsutsugamushi infection.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos neglected tropical diseases
Publication Year Start




PMID- 28723951
OWN - NLM
STAT- Publisher
DA  - 20170720
LR  - 20170720
IS  - 1935-2735 (Electronic)
IS  - 1935-2727 (Linking)
VI  - 11
IP  - 7
DP  - 2017 Jul 19
TI  - CD8+ T cells provide immune protection against murine disseminated
      endotheliotropic Orientia tsutsugamushi infection.
PG  - e0005763
LID - 10.1371/journal.pntd.0005763 [doi]
AB  - Scrub typhus, caused by a Gram-negative obligately intracellular coccobacillus,
      Orientia tsutsugamushi, is a long neglected but important tropical disease.
      Orientia tsutsugamushi causes illness in one million people each year, and 1
      billion people are at risk. Without appropriate diagnosis and treatment, the
      disease can cause severe multiorgan failure with a case fatality rate of 7-15%.
      The current gaps in knowledge of immunity include the unknown mechanisms of host 
      immunity to O. tsutsugamushi. Using an intravenous (i.v.) disseminated infection 
      mouse model, we observed that more CD8+ T cells than CD4+ T cells were present in
      the spleen of infected mice at 12 dpi. We also determined that Treg cells and the
      proportion of T cells producing IL-10 were significantly increased from 6 dpi,
      which correlated with the onset of illness, body weight loss, and increased
      bacterial loads. We further studied CD8-/-, MHC I-/- and wild type control (WT)
      C57BL/6J mice to determine the importance of CD8+ T cells and MHC I molecules.
      After infection with an ordinarily sub-lethal dose of O. tsutsugamushi, all
      CD8-/- and MHC I-/- mice were moribund between 12 and 15 dpi, whereas all WT mice
      survived. Bacterial loads in the lung, kidney, liver and spleen of CD8-/- and MHC
      I-/- mice were significantly greater than those in WT mice. Interferon-gamma
      (IFN-gamma) and granzyme B mRNA levels in the liver of CD8-/- and MHC I-/- mice
      were significantly greater than in WT mice. In addition, more severe
      histopathologic lesions were observed in CD8-/- mice. Finally, adoptive transfer 
      confirmed a major role of immune CD8+ T cells as well as a less effective
      contribution by immune CD8 T cell-depleted splenocytes in protection against O.
      tsutsugamushi infection. These studies demonstrated the critical importance of
      CD8+ T cells in the host immune response during O. tsutsugamushi infection.
FAU - Xu, Guang
AU  - Xu G
AD  - Department of Pathology, The University of Texas Medical Branch, Galveston,
      Texas, United Sates of America.
FAU - Mendell, Nicole L
AU  - Mendell NL
AD  - Department of Pathology, The University of Texas Medical Branch, Galveston,
      Texas, United Sates of America.
FAU - Liang, Yuejin
AU  - Liang Y
AD  - Department of Microbiology and Immunology, The University of Texas Medical
      Branch, Galveston, Texas, United Sates of America.
FAU - Shelite, Thomas R
AU  - Shelite TR
AD  - Department of Internal Medicine, Division of Infectious Diseases, The University 
      of Texas Medical Branch, Galveston, Texas, United Sates of America.
FAU - Goez-Rivillas, Yenny
AU  - Goez-Rivillas Y
AD  - Department of Pathology, The University of Texas Medical Branch, Galveston,
      Texas, United Sates of America.
FAU - Soong, Lynn
AU  - Soong L
AD  - Department of Pathology, The University of Texas Medical Branch, Galveston,
      Texas, United Sates of America.
AD  - Department of Microbiology and Immunology, The University of Texas Medical
      Branch, Galveston, Texas, United Sates of America.
FAU - Bouyer, Donald H
AU  - Bouyer DH
AD  - Department of Pathology, The University of Texas Medical Branch, Galveston,
      Texas, United Sates of America.
FAU - Walker, David H
AU  - Walker DH
AUID- ORCID: http://orcid.org/0000-0002-3309-4360
AD  - Department of Pathology, The University of Texas Medical Branch, Galveston,
      Texas, United Sates of America.
AD  - Department of Microbiology and Immunology, The University of Texas Medical
      Branch, Galveston, Texas, United Sates of America.
LA  - eng
PT  - Journal Article
DEP - 20170719
PL  - United States
TA  - PLoS Negl Trop Dis
JT  - PLoS neglected tropical diseases
JID - 101291488
EDAT- 2017/07/21 06:00
MHDA- 2017/07/21 06:00
CRDT- 2017/07/21 06:00
PHST- 2017/02/09 [received]
PHST- 2017/06/30 [accepted]
AID - 10.1371/journal.pntd.0005763 [doi]
AID - PNTD-D-17-00210 [pii]
PST - aheadofprint
SO  - PLoS Negl Trop Dis. 2017 Jul 19;11(7):e0005763. doi:
      10.1371/journal.pntd.0005763.