Virus Infections Incite Pain Hypersensitivity by Inducing Indoleamine 2,3 Dioxygenase

Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brai...

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Published in:	PLoS pathogens Vol. 12; no. 5; p. e1005615
Main Authors:	Huang, Lei, Ou, Rong, Rabelo de Souza, Guilherme, Cunha, Thiago M., Lemos, Henrique, Mohamed, Eslam, Li, Lingqian, Pacholczyk, Gabriela, Randall, Janice, Munn, David H., Mellor, Andrew L.
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 01.05.2016 Public Library of Science (PLoS)
Subjects:	Animals Biology and Life Sciences Brain research Cytokines Disease Models, Animal Enzymes Experiments Flow Cytometry Genetic aspects Health aspects HIV Human immunodeficiency virus Hyperalgesia - enzymology Hyperalgesia - etiology Hypersensitivity Hypotheses Indoleamine-Pyrrole 2,3,-Dioxygenase - biosynthesis Infections Inflammation Influenza Influenza A virus Kynurenine - metabolism Laboratory animals Leukemia Medicine and Health Sciences Mice Orthomyxoviridae Pain Pain management Physiological aspects Polymerase Chain Reaction Research and Analysis Methods Retroviridae Rodents Spinal cord Spleen Tryptophan Virus diseases Virus Diseases - complications Viruses
ISSN:	1553-7374, 1553-7366, 1553-7374
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Abstract	Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brain mediated by indoleamine 2,3 dioxygenase (IDO). Here we show that acute influenza A virus (IAV) and chronic murine leukemia retrovirus (MuLV) infections, which stimulate robust IDO expression in lungs and lymphoid tissues, induced acute or chronic pain hypersensitivity, respectively. In contrast, virus-induced pain hypersensitivity did not manifest in mice lacking intact IDO1 genes. Spleen IDO activity increased markedly as MuLV infections progressed, while IDO1 expression was not elevated significantly in brain or spinal cord (CNS) tissues. Moreover, kynurenine (Kyn), a tryptophan catabolite made by cells expressing IDO, incited pain hypersensitivity in uninfected IDO1-deficient mice and Kyn potentiated pain hypersensitivity due to MuLV infection. MuLV infection stimulated selective IDO expression by a discreet population of spleen cells expressing both B cell (CD19) and dendritic cell (CD11c) markers (CD19+ DCs). CD19+ DCs were more susceptible to MuLV infection than B cells or conventional (CD19neg) DCs, proliferated faster than B cells from early stages of MuLV infection and exhibited mature antigen presenting cell (APC) phenotypes, unlike conventional (CD19neg) DCs. Moreover, interactions with CD4 T cells were necessary to sustain functional IDO expression by CD19+ DCs in vitro and in vivo. Splenocytes from MuLV-infected IDO1-sufficient mice induced pain hypersensitivity in uninfected IDO1-deficient recipient mice, while selective in vivo depletion of DCs alleviated pain hypersensitivity in MuLV-infected IDO1-sufficient mice and led to rapid reduction in splenomegaly, a hallmark of MuLV immune pathogenesis. These findings reveal critical roles for CD19+ DCs expressing IDO in host responses to MuLV infection that enhance pain hypersensitivity and cause immune pathology. Collectively, our findings support the hypothesis elevated IDO activity in non-CNS due to virus infections causes pain hypersensitivity mediated by Kyn. Previously unappreciated links between host immune responses to virus infections and pain sensitivity suggest that IDO inhibitors may alleviate heightened pain sensitivity during infections.
AbstractList	Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brain mediated by indoleamine 2,3 dioxygenase (IDO). Here we show that acute influenza A virus (IAV) and chronic murine leukemia retrovirus (MuLV) infections, which stimulate robust IDO expression in lungs and lymphoid tissues, induced acute or chronic pain hypersensitivity, respectively. In contrast, virus-induced pain hypersensitivity did not manifest in mice lacking intact IDO1 genes. Spleen IDO activity increased markedly as MuLV infections progressed, while IDO1 expression was not elevated significantly in brain or spinal cord (CNS) tissues. Moreover, kynurenine (Kyn), a tryptophan catabolite made by cells expressing IDO, incited pain hypersensitivity in uninfected IDO1-deficient mice and Kyn potentiated pain hypersensitivity due to MuLV infection. MuLV infection stimulated selective IDO expression by a discreet population of spleen cells expressing both B cell (CD19) and dendritic cell (CD11c) markers (CD19+ DCs). CD19+ DCs were more susceptible to MuLV infection than B cells or conventional (CD19neg) DCs, proliferated faster than B cells from early stages of MuLV infection and exhibited mature antigen presenting cell (APC) phenotypes, unlike conventional (CD19neg) DCs. Moreover, interactions with CD4 T cells were necessary to sustain functional IDO expression by CD19+ DCs in vitro and in vivo. Splenocytes from MuLV-infected IDO1-sufficient mice induced pain hypersensitivity in uninfected IDO1-deficient recipient mice, while selective in vivo depletion of DCs alleviated pain hypersensitivity in MuLV-infected IDO1-sufficient mice and led to rapid reduction in splenomegaly, a hallmark of MuLV immune pathogenesis. These findings reveal critical roles for CD19+ DCs expressing IDO in host responses to MuLV infection that enhance pain hypersensitivity and cause immune pathology. Collectively, our findings support the hypothesis elevated IDO activity in non-CNS due to virus infections causes pain hypersensitivity mediated by Kyn. Previously unappreciated links between host immune responses to virus infections and pain sensitivity suggest that IDO inhibitors may alleviate heightened pain sensitivity during infections. Chronic pain is a factor in diseases that afflict many people, yet the underlying causes of pain are poorly understood. Here we assess the effects of virus infections on pain sensitivity in mice. Infecting mice with two different viruses, influenza and mouse leukemia virus (MuLV) increased pain sensitivity. Influenza infection caused transient increase in pain sensitivity, which returned to normal levels after infections were cleared. However persistent MuLV infections caused sustained increase in pain sensitivity. Virus-induced pain sensitivity was reduced substantially in mice lacking the enzyme indoleamine 2,3 dioxygenase (IDO), which degrades the amino acid tryptophan. Moreover a natural compound produced by cells expressing IDO enhanced pain sensitivity when administered to mice lacking IDO genes. Thus cells expressing IDO caused increased pain sensitivity in infected mice. A distinctive cell type expressed IDO selectively and accumulated in spleens of MuLV-infected mice. Transfer of spleen cells from MuLV-infected mice caused increased pain sensitivity in uninfected mice while eliminating specific cells in MuLV-infected mice abolished enhanced pain sensitivity. Our findings show that host immune responses to virus infections cause increased pain sensitivity and suggest novel ways to alleviate pain during infections. Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brain mediated by indoleamine 2,3 dioxygenase (IDO). Here we show that acute influenza A virus (IAV) and chronic murine leukemia retrovirus (MuLV) infections, which stimulate robust IDO expression in lungs and lymphoid tissues, induced acute or chronic pain hypersensitivity, respectively. In contrast, virus-induced pain hypersensitivity did not manifest in mice lacking intact IDO1 genes. Spleen IDO activity increased markedly as MuLV infections progressed, while IDO1 expression was not elevated significantly in brain or spinal cord (CNS) tissues. Moreover, kynurenine (Kyn), a tryptophan catabolite made by cells expressing IDO, incited pain hypersensitivity in uninfected IDO1-deficient mice and Kyn potentiated pain hypersensitivity due to MuLV infection. MuLV infection stimulated selective IDO expression by a discreet population of spleen cells expressing both B cell (CD19) and dendritic cell (CD11c) markers (CD19.sup.+ DCs). CD19.sup.+ DCs were more susceptible to MuLV infection than B cells or conventional (CD19.sup.neg) DCs, proliferated faster than B cells from early stages of MuLV infection and exhibited mature antigen presenting cell (APC) phenotypes, unlike conventional (CD19.sup.neg) DCs. Moreover, interactions with CD4 T cells were necessary to sustain functional IDO expression by CD19.sup.+ DCs in vitro and in vivo. Splenocytes from MuLV-infected IDO1-sufficient mice induced pain hypersensitivity in uninfected IDO1-deficient recipient mice, while selective in vivo depletion of DCs alleviated pain hypersensitivity in MuLV-infected IDO1-sufficient mice and led to rapid reduction in splenomegaly, a hallmark of MuLV immune pathogenesis. These findings reveal critical roles for CD19.sup.+ DCs expressing IDO in host responses to MuLV infection that enhance pain hypersensitivity and cause immune pathology. Collectively, our findings support the hypothesis elevated IDO activity in non-CNS due to virus infections causes pain hypersensitivity mediated by Kyn. Previously unappreciated links between host immune responses to virus infections and pain sensitivity suggest that IDO inhibitors may alleviate heightened pain sensitivity during infections. Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brain mediated by indoleamine 2,3 dioxygenase (IDO). Here we show that acute influenza A virus (IAV) and chronic murine leukemia retrovirus (MuLV) infections, which stimulate robust IDO expression in lungs and lymphoid tissues, induced acute or chronic pain hypersensitivity, respectively. In contrast, virus-induced pain hypersensitivity did not manifest in mice lacking intact IDO1 genes. Spleen IDO activity increased markedly as MuLV infections progressed, while IDO1 expression was not elevated significantly in brain or spinal cord (CNS) tissues. Moreover, kynurenine (Kyn), a tryptophan catabolite made by cells expressing IDO, incited pain hypersensitivity in uninfected IDO1-deficient mice and Kyn potentiated pain hypersensitivity due to MuLV infection. MuLV infection stimulated selective IDO expression by a discreet population of spleen cells expressing both B cell (CD19) and dendritic cell (CD11c) markers (CD19+ DCs). CD19+ DCs were more susceptible to MuLV infection than B cells or conventional (CD19neg) DCs, proliferated faster than B cells from early stages of MuLV infection and exhibited mature antigen presenting cell (APC) phenotypes, unlike conventional (CD19neg) DCs. Moreover, interactions with CD4 T cells were necessary to sustain functional IDO expression by CD19+ DCs in vitro and in vivo. Splenocytes from MuLV-infected IDO1-sufficient mice induced pain hypersensitivity in uninfected IDO1-deficient recipient mice, while selective in vivo depletion of DCs alleviated pain hypersensitivity in MuLV-infected IDO1-sufficient mice and led to rapid reduction in splenomegaly, a hallmark of MuLV immune pathogenesis. These findings reveal critical roles for CD19+ DCs expressing IDO in host responses to MuLV infection that enhance pain hypersensitivity and cause immune pathology. Collectively, our findings support the hypothesis elevated IDO activity in non-CNS due to virus infections causes pain hypersensitivity mediated by Kyn. Previously unappreciated links between host immune responses to virus infections and pain sensitivity suggest that IDO inhibitors may alleviate heightened pain sensitivity during infections. Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brain mediated by indoleamine 2,3 dioxygenase (IDO). Here we show that acute influenza A virus (IAV) and chronic murine leukemia retrovirus (MuLV) infections, which stimulate robust IDO expression in lungs and lymphoid tissues, induced acute or chronic pain hypersensitivity, respectively. In contrast, virus-induced pain hypersensitivity did not manifest in mice lacking intact IDO1 genes. Spleen IDO activity increased markedly as MuLV infections progressed, while IDO1 expression was not elevated significantly in brain or spinal cord (CNS) tissues. Moreover, kynurenine (Kyn), a tryptophan catabolite made by cells expressing IDO, incited pain hypersensitivity in uninfected IDO1-deficient mice and Kyn potentiated pain hypersensitivity due to MuLV infection. MuLV infection stimulated selective IDO expression by a discreet population of spleen cells expressing both B cell (CD19) and dendritic cell (CD11c) markers (CD19+ DCs). CD19+ DCs were more susceptible to MuLV infection than B cells or conventional (CD19neg) DCs, proliferated faster than B cells from early stages of MuLV infection and exhibited mature antigen presenting cell (APC) phenotypes, unlike conventional (CD19neg) DCs. Moreover, interactions with CD4 T cells were necessary to sustain functional IDO expression by CD19+ DCs in vitro and in vivo. Splenocytes from MuLV-infected IDO1-sufficient mice induced pain hypersensitivity in uninfected IDO1-deficient recipient mice, while selective in vivo depletion of DCs alleviated pain hypersensitivity in MuLV-infected IDO1-sufficient mice and led to rapid reduction in splenomegaly, a hallmark of MuLV immune pathogenesis. These findings reveal critical roles for CD19+ DCs expressing IDO in host responses to MuLV infection that enhance pain hypersensitivity and cause immune pathology. Collectively, our findings support the hypothesis elevated IDO activity in non-CNS due to virus infections causes pain hypersensitivity mediated by Kyn. Previously unappreciated links between host immune responses to virus infections and pain sensitivity suggest that IDO inhibitors may alleviate heightened pain sensitivity during infections.Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brain mediated by indoleamine 2,3 dioxygenase (IDO). Here we show that acute influenza A virus (IAV) and chronic murine leukemia retrovirus (MuLV) infections, which stimulate robust IDO expression in lungs and lymphoid tissues, induced acute or chronic pain hypersensitivity, respectively. In contrast, virus-induced pain hypersensitivity did not manifest in mice lacking intact IDO1 genes. Spleen IDO activity increased markedly as MuLV infections progressed, while IDO1 expression was not elevated significantly in brain or spinal cord (CNS) tissues. Moreover, kynurenine (Kyn), a tryptophan catabolite made by cells expressing IDO, incited pain hypersensitivity in uninfected IDO1-deficient mice and Kyn potentiated pain hypersensitivity due to MuLV infection. MuLV infection stimulated selective IDO expression by a discreet population of spleen cells expressing both B cell (CD19) and dendritic cell (CD11c) markers (CD19+ DCs). CD19+ DCs were more susceptible to MuLV infection than B cells or conventional (CD19neg) DCs, proliferated faster than B cells from early stages of MuLV infection and exhibited mature antigen presenting cell (APC) phenotypes, unlike conventional (CD19neg) DCs. Moreover, interactions with CD4 T cells were necessary to sustain functional IDO expression by CD19+ DCs in vitro and in vivo. Splenocytes from MuLV-infected IDO1-sufficient mice induced pain hypersensitivity in uninfected IDO1-deficient recipient mice, while selective in vivo depletion of DCs alleviated pain hypersensitivity in MuLV-infected IDO1-sufficient mice and led to rapid reduction in splenomegaly, a hallmark of MuLV immune pathogenesis. These findings reveal critical roles for CD19+ DCs expressing IDO in host responses to MuLV infection that enhance pain hypersensitivity and cause immune pathology. Collectively, our findings support the hypothesis elevated IDO activity in non-CNS due to virus infections causes pain hypersensitivity mediated by Kyn. Previously unappreciated links between host immune responses to virus infections and pain sensitivity suggest that IDO inhibitors may alleviate heightened pain sensitivity during infections. Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain hypersensitivity in rodents treated to induce chronic inflammation in peripheral tissues was linked to enhanced tryptophan catabolism in brain mediated by indoleamine 2,3 dioxygenase (IDO). Here we show that acute influenza A virus (IAV) and chronic murine leukemia retrovirus (MuLV) infections, which stimulate robust IDO expression in lungs and lymphoid tissues, induced acute or chronic pain hypersensitivity, respectively. In contrast, virus-induced pain hypersensitivity did not manifest in mice lacking intact IDO1 genes. Spleen IDO activity increased markedly as MuLV infections progressed, while IDO1 expression was not elevated significantly in brain or spinal cord (CNS) tissues. Moreover, kynurenine (Kyn), a tryptophan catabolite made by cells expressing IDO, incited pain hypersensitivity in uninfected IDO1-deficient mice and Kyn potentiated pain hypersensitivity due to MuLV infection. MuLV infection stimulated selective IDO expression by a discreet population of spleen cells expressing both B cell (CD19) and dendritic cell (CD11c) markers (CD19+ DCs). CD19+ DCs were more susceptible to MuLV infection than B cells or conventional (CD19neg) DCs, proliferated faster than B cells from early stages of MuLV infection and exhibited mature antigen presenting cell (APC) phenotypes, unlike conventional (CD19neg) DCs. Moreover, interactions with CD4 T cells were necessary to sustain functional IDO expression by CD19+ DCs in vitro and in vivo. Splenocytes from MuLV-infected IDO1-sufficient mice induced pain hypersensitivity in uninfected IDO1-deficient recipient mice, while selective in vivo depletion of DCs alleviated pain hypersensitivity in MuLV-infected IDO1-sufficient mice and led to rapid reduction in splenomegaly, a hallmark of MuLV immune pathogenesis. These findings reveal critical roles for CD19+ DCs expressing IDO in host responses to MuLV infection that enhance pain hypersensitivity and cause immune pathology. Collectively, our findings support the hypothesis elevated IDO activity in non-CNS due to virus infections causes pain hypersensitivity mediated by Kyn. Previously unappreciated links between host immune responses to virus infections and pain sensitivity suggest that IDO inhibitors may alleviate heightened pain sensitivity during infections.
Audience	Academic
Author	Lemos, Henrique Munn, David H. Huang, Lei Ou, Rong Randall, Janice Mohamed, Eslam Rabelo de Souza, Guilherme Li, Lingqian Pacholczyk, Gabriela Mellor, Andrew L. Cunha, Thiago M.
AuthorAffiliation	2 Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil 1 Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Augusta University, Augusta, Georgia, United States of America Icahn School of Medicine at Mount Sinai, UNITED STATES
AuthorAffiliation_xml	– name: 1 Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Augusta University, Augusta, Georgia, United States of America – name: Icahn School of Medicine at Mount Sinai, UNITED STATES – name: 2 Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
Author_xml	– sequence: 1 givenname: Lei surname: Huang fullname: Huang, Lei – sequence: 2 givenname: Rong surname: Ou fullname: Ou, Rong – sequence: 3 givenname: Guilherme surname: Rabelo de Souza fullname: Rabelo de Souza, Guilherme – sequence: 4 givenname: Thiago M. surname: Cunha fullname: Cunha, Thiago M. – sequence: 5 givenname: Henrique surname: Lemos fullname: Lemos, Henrique – sequence: 6 givenname: Eslam surname: Mohamed fullname: Mohamed, Eslam – sequence: 7 givenname: Lingqian surname: Li fullname: Li, Lingqian – sequence: 8 givenname: Gabriela surname: Pacholczyk fullname: Pacholczyk, Gabriela – sequence: 9 givenname: Janice surname: Randall fullname: Randall, Janice – sequence: 10 givenname: David H. surname: Munn fullname: Munn, David H. – sequence: 11 givenname: Andrew L. surname: Mellor fullname: Mellor, Andrew L.
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/27168185$$D View this record in MEDLINE/PubMed
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ContentType	Journal Article
Copyright	COPYRIGHT 2016 Public Library of Science 2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Huang L, Ou R, Rabelo de Souza G, Cunha TM, Lemos H, Mohamed E, et al. (2016) Virus Infections Incite Pain Hypersensitivity by Inducing Indoleamine 2,3 Dioxygenase. PLoS Pathog 12(5): e1005615. doi:10.1371/journal.ppat.1005615 2016 Huang et al 2016 Huang et al 2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Huang L, Ou R, Rabelo de Souza G, Cunha TM, Lemos H, Mohamed E, et al. (2016) Virus Infections Incite Pain Hypersensitivity by Inducing Indoleamine 2,3 Dioxygenase. PLoS Pathog 12(5): e1005615. doi:10.1371/journal.ppat.1005615
Copyright_xml	– notice: COPYRIGHT 2016 Public Library of Science – notice: 2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Huang L, Ou R, Rabelo de Souza G, Cunha TM, Lemos H, Mohamed E, et al. (2016) Virus Infections Incite Pain Hypersensitivity by Inducing Indoleamine 2,3 Dioxygenase. PLoS Pathog 12(5): e1005615. doi:10.1371/journal.ppat.1005615 – notice: 2016 Huang et al 2016 Huang et al – notice: 2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Huang L, Ou R, Rabelo de Souza G, Cunha TM, Lemos H, Mohamed E, et al. (2016) Virus Infections Incite Pain Hypersensitivity by Inducing Indoleamine 2,3 Dioxygenase. PLoS Pathog 12(5): e1005615. doi:10.1371/journal.ppat.1005615
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DocumentTitleAlternate	Virus Infections Induce Pain via IDO
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Current address: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK. Conceived and designed the experiments: LH GRdS ALM. Performed the experiments: LH RO GRdS HL EM LL GP JR. Analyzed the data: LH RO GRdS TMC HL EM LL DHM ALM. Wrote the paper: LH TMC DHM ALM. I have read the journal's policy and the authors of this manuscript have the following competing interests: ALM and DHM serve as consultants for NewLink Genetics Inc. and receive remuneration from this source. The authors declare no additional competing financial interests. This does not alter our adherence to all PLOS policies on sharing data and materials.
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Snippet	Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic pain... Increased pain sensitivity is a comorbidity associated with many clinical diseases, though the underlying causes are poorly understood. Recently, chronic...
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SubjectTerms	Animals Biology and Life Sciences Brain research Cytokines Disease Models, Animal Enzymes Experiments Flow Cytometry Genetic aspects Health aspects HIV Human immunodeficiency virus Hyperalgesia - enzymology Hyperalgesia - etiology Hypersensitivity Hypotheses Indoleamine-Pyrrole 2,3,-Dioxygenase - biosynthesis Infections Inflammation Influenza Influenza A virus Kynurenine - metabolism Laboratory animals Leukemia Medicine and Health Sciences Mice Orthomyxoviridae Pain Pain management Physiological aspects Polymerase Chain Reaction Research and Analysis Methods Retroviridae Rodents Spinal cord Spleen Tryptophan Virus diseases Virus Diseases - complications Viruses
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Title	Virus Infections Incite Pain Hypersensitivity by Inducing Indoleamine 2,3 Dioxygenase
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