scholarly journals Interferon Response Factors 3 and 7 Protect against Chikungunya Virus Hemorrhagic Fever and Shock

2012 ◽  
Vol 86 (18) ◽  
pp. 9888-9898 ◽  
Author(s):  
Penny A. Rudd ◽  
Jane Wilson ◽  
Joy Gardner ◽  
Thibaut Larcher ◽  
Candice Babarit ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
Mononuclear Cells ◽  
Severe Disease ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Interferon Response ◽  
Wild Type ◽  
Chikv Infection ◽  
Response Factors ◽  
Adult Mice

Chikungunya virus (CHIKV) infections can produce severe disease and mortality. Here we show that CHIKV infection of adult mice deficient in interferon response factors 3 and 7 (IRF3/7−/−) is lethal. Mortality was associated with undetectable levels of alpha/beta interferon (IFN-α/β) in serum, ∼50- and ∼10-fold increases in levels of IFN-γ and tumor necrosis factor (TNF), respectively, increased virus replication, edema, vasculitis, hemorrhage, fever followed by hypothermia, oliguria, thrombocytopenia, and raised hematocrits. These features are consistent with hemorrhagic shock and were also evident in infected IFN-α/β receptor-deficient mice.In situhybridization suggested CHIKV infection of endothelium, fibroblasts, skeletal muscle, mononuclear cells, chondrocytes, and keratinocytes in IRF3/7−/−mice; all but the latter two stained positive in wild-type mice. Vaccination protected IRF3/7−/−mice, suggesting that defective antibody responses were not responsible for mortality. IPS-1- and TRIF-dependent pathways were primarily responsible for IFN-α/β induction, with IRF7 being upregulated >100-fold in infected wild-type mice. These studies suggest that inadequate IFN-α/β responses following virus infection can be sufficient to induce hemorrhagic fever and shock, a finding with implications for understanding severe CHIKV disease and dengue hemorrhagic fever/dengue shock syndrome.

scholarly journals Effects of Chikungunya virus immunity on Mayaro virus disease and epidemic potential

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Emily M. Webb ◽  
Sasha R. Azar ◽  
Sherry L. Haller ◽  
Rose M. Langsjoen ◽  
Candace E. Cuthbert ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Chikungunya Virus ◽  
Semliki Forest Virus ◽  
Virus Disease ◽  
Cross Protection ◽  
Health Concern ◽  
Antigenic Relationship ◽  
Wild Type ◽  
Chikv Infection ◽  
Mayaro Virus

AbstractMayaro virus (MAYV) causes an acute febrile illness similar to that produced by chikungunya virus (CHIKV), an evolutionary relative in the Semliki Forest virus complex of alphaviruses. MAYV emergence is typically sporadic, but recent isolations and outbreaks indicate that the virus remains a public health concern. Given the close phylogenetic and antigenic relationship between CHIKV and MAYV, and widespread distribution of CHIKV, we hypothesized that prior CHIKV immunity may affect MAYV pathogenesis and/or influence its emergence potential. We pre-exposed immunocompetent C57BL/6 and immunocompromised A129 or IFNAR mice to wild-type CHIKV, two CHIKV vaccines, or a live-attenuated MAYV vaccine, and challenged with MAYV. We observed strong cross-protection against MAYV for mice pre-exposed to wild-type CHIKV, and moderately but significantly reduced cross-protection from CHIKV-vaccinated animals. Immunity to other alphavirus or flavivirus controls provided no protection against MAYV disease or viremia. Mechanistic studies suggested that neutralizing antibodies alone can mediate this protection, with T-cells having no significant effect on diminishing disease. Finally, human sera obtained from naturally acquired CHIKV infection cross-neutralized MAYV at high titers in vitro. Altogether, our data suggest that CHIKV infection can confer cross-protective effects against MAYV, and the resultant reduction in viremia may limit the emergence potential of MAYV.

scholarly journals A STUDY OF MULTIORGAN DYSFUNCTION IN PATIENTS WITH DENGUE AND ITS CLINICO- HAEMATOLOGICAL CORRELATION WITH SEVERITY.

2017 ◽  
Vol 10 (2) ◽  
pp. 218
Author(s):  
Jadumani Nayak ◽  
Sudeshna Behera ◽  
Shrikanta Kumar Swain ◽  
Smaraka Ranjan Panda
Keyword(s):  
Liver Enzymes ◽  
Severe Disease ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Severe Form ◽  
Activated Partial Thromboplastin Time ◽  
Organ System ◽  
Multiorgan Dysfunction ◽  
Major Organ ◽  
Cns Dysfunction

Objective: To study of multiorgan dysfunction in patients with dengue and to correlate the severity and clinical outcome with different haematological parameters.Material & methods: All suspected cases of dengue admitted to Medicine dept within 1 year period were evaluated & classified as DF(dengue fever), DHF(dengue hemorrhagic fever), DSS(dengue shock syndrome).Results: out of total 150 cases,108 cases were classified as DF, 31 cases as DHF and 11 cases as DSS. Liver involvement was seen in 97.33% cases. Jaundice was observed in 10 cases(6.6%),abnormal AST(aspartate transaminase) in 146 (97.33 %) cases and abnormal ALT(alanine transaminase)in 126 (84%) cases. Bleeding manifestations was reported in 61 patients (40.6%).Presence of GI Bleeding in 17 patients (11.3%) was related to severe disease. Thrombocytopenia was present in 25% of DF cases, and in all cases of DHF and DS. Among these, PT(prothrombin time) was prolonged in 10 cases and aPTT(activated partial thromboplastin time) in 47 patients. Serum Fibrinogen was low in 28.57 % of patients. Multiorgan dysfunction was observed in the form of simultaneous hepatic and renal dysfunction in 3.33 % of cases, hepatic and CNS dysfunction in 2.66% of cases, hepatic & cardiac dysfunction in 2% of cases and all the organ system dysfunction in 0.67% of cases.Conclusion: The extent of rise of liver enzymes, PT, aPTT & fall of serum fibrinogen, and degree of thrombocytopenia correlated with disease severity. Acute renal failure, encephalitis and myocarditis are manifestations of severe form of dengue. Major organ involvement may occur in simple DF also.

scholarly journals Attenuation of V- or C-Defective Measles Viruses: Infection Control by the Inflammatory and Interferon Responses of Rhesus Monkeys

2008 ◽  
Vol 82 (11) ◽  
pp. 5359-5367 ◽  
Author(s):  
Patricia Devaux ◽  
Gregory Hodge ◽  
Michael B. McChesney ◽  
Roberto Cattaneo
Keyword(s):  
Immune Responses ◽  
Measles Virus ◽  
Mononuclear Cells ◽  
Interferon Response ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Adaptive Immune Responses ◽  
C Protein ◽  
Adaptive Immune

ABSTRACT Patients recruited in virus-based cancer clinical trials and immunocompromised individuals in need of vaccination would profit from viral strains with defined attenuation mechanisms. We generated measles virus (MV) strains defective for the expression of either the V protein, a modulator of the innate immune response, or the C protein, which has multiple functions. The virulence of these strains was compared with that of the parental wild-type MV in a natural host, Macaca mulatta. Skin rash, viremia, and the strength of the innate and adaptive immune responses were characterized in groups of six animals. Replication of V- or C-protein-defective viruses was short-lived and reached lower levels in peripheral blood mononuclear cells and lymphatic organs compared to the wild-type virus; none of the mutants reverted to the wild type. The neutralizing antibody titers and MV-specific T-cell responses were equivalent in monkeys infected with the viral strains tested, documenting strong adaptive immune responses. In contrast, the inflammatory response was better controlled by wild-type MV, as revealed by inhibition of interleukin-6 and tumor necrosis factor alpha transcription. The interferon response was also better controlled by the wild-type virus than by the defective viruses. Since V- and C-defective MVs induce strong adaptive immune responses while spreading less efficiently, they may be developed as vaccines for immunocompromised individuals. Moreover, MV unable to interact with single innate immunity proteins may be developed for preferential replication in tumors with specific contexts of vulnerability.

scholarly journals Dengue Virus Pathogenesis: an Integrated View

2009 ◽  
Vol 22 (4) ◽  
pp. 564-581 ◽  
Author(s):  
Byron E. E. Martina ◽  
Penelope Koraka ◽  
Albert D. M. E. Osterhaus
Keyword(s):  
Dengue Virus ◽  
Severe Disease ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Host Responses ◽  
Individual Risk ◽  
Cell Tropism ◽  
Viral Virulence ◽  
Vascular Beds ◽  
Personalized Approach

SUMMARY Much remains to be learned about the pathogenesis of the different manifestations of dengue virus (DENV) infections in humans. They may range from subclinical infection to dengue fever, dengue hemorrhagic fever (DHF), and eventually dengue shock syndrome (DSS). As both cell tropism and tissue tropism of DENV are considered major determinants in the pathogenesis of dengue, there is a critical need for adequate tropism assays, animal models, and human autopsy data. More than 50 years of research on dengue has resulted in a host of literature, which strongly suggests that the pathogenesis of DHF and DSS involves viral virulence factors and detrimental host responses, collectively resulting in abnormal hemostasis and increased vascular permeability. Differential targeting of specific vascular beds is likely to trigger the localized vascular hyperpermeability underlying DSS. A personalized approach to the study of pathogenesis will elucidate the basis of individual risk for development of DHF and DSS as well as identify the genetic and environmental bases for differences in risk for development of severe disease.

scholarly journals A Review of Chikungunya Virus-induced Arthralgia: Clinical Manifestations, Therapeutics, and Pathogenesis

2016 ◽  
Vol 10 (1) ◽  
pp. 129-140 ◽  
Author(s):  
Brad A. Goupil ◽  
Christopher N. Mores
Keyword(s):  
Clinical Research ◽  
Chikungunya Virus ◽  
Severe Disease ◽  
Clinical Manifestations ◽  
Western Hemisphere ◽  
Joint Disease ◽  
Chikv Infection ◽  
Initial Infection ◽  
Current State

Background:Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that circulates predominantly in tropical and subtropical regions, potentially affecting over 1 billion people. Recently, an outbreak began in the western hemisphere and has resulted in over 1.8 million reported suspected cases. Infection often results in severe fever, rash and debilitating polyarthralgia lasting weeks to months. Additionally, the current literature reports that CHIKV can result in a severe chronic arthralgia and/or arthritis that can last months to years following the initial infection.Objective:The purpose of this review is to evaluate the literature and summarize the current state of knowledge regarding CHIKV-associated disease, including clinical presentation, diagnosis, risk factors for development of severe disease, treatment, and pathogenesis in human patients. Additionally, recommendations are presented regarding avenues for clinical research to help further elucidate the pathogenesis of joint disease associated with CHIKV infection.Conclusion:While there is an association between initial CHIKV infection and acute disease, a causal relationship with development of chronic arthralgia has not been established at this time. Potential causes of chronic CHIKV-induced arthritis have been postulated, including viral persistence, induction of autoimmune disease, and exacerbation of pre-existing joint disease. While there are numerous reports of chronic CHIKV-associated arthralgia and/or arthritis, there is currently no evidence of a definitive link between initial infection and development of chronic disease. Additional, prospective clinical research on CHIKV-associated disease is necessary to further determine the potential role of virus and development of chronic joint disease.

scholarly journals γδ T Cells Play a Protective Role in Chikungunya Virus-Induced Disease

2015 ◽  
Vol 90 (1) ◽  
pp. 433-443 ◽  
Author(s):  
Kristin M. Long ◽  
Martin T. Ferris ◽  
Alan C. Whitmore ◽  
Stephanie A. Montgomery ◽  
Lance R. Thurlow ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chikungunya Virus ◽  
Joint Damage ◽  
Γδ T Cells ◽  
The United States ◽  
Protective Role ◽  
Γδ T Cell ◽  
Wild Type ◽  
Chikv Infection

ABSTRACTChikungunya virus (CHIKV) is an alphavirus responsible for causing epidemic outbreaks of polyarthralgia in humans. Because CHIKV is initially introduced via the skin, where γδ T cells are prevalent, we evaluated the response of these cells to CHIKV infection. CHIKV infection led to a significant increase in γδ T cells in the infected foot and draining lymph node that was associated with the production of proinflammatory cytokines and chemokines in C57BL/6J mice. γδ T cell−/−mice demonstrated exacerbated CHIKV disease characterized by less weight gain and greater foot swelling than occurred in wild-type mice, as well as a transient increase in monocytes and altered cytokine/chemokine expression in the foot. Histologically, γδ T cell−/−mice had increased inflammation-mediated oxidative damage in the ipsilateral foot and ankle joint compared to wild-type mice which was independent of differences in CHIKV replication. These results suggest that γδ T cells play a protective role in limiting the CHIKV-induced inflammatory response and subsequent tissue and joint damage.IMPORTANCERecent epidemics, including the 2004 to 2007 outbreak and the spread of CHIKV to naive populations in the Caribbean and Central and South America with resultant cases imported into the United States, have highlighted the capacity of CHIKV to cause explosive epidemics where the virus can spread to millions of people and rapidly move into new areas. These studies identified γδ T cells as important to both recruitment of key inflammatory cell populations and dampening the tissue injury due to oxidative stress. Given the importance of these cells in the early response to CHIKV, this information may inform the development of CHIKV vaccines and therapeutics.

scholarly journals Interferon-Dependent Immunity Is Essential for Resistance to Primary Dengue Virus Infection in Mice, Whereas T- and B-Cell-Dependent Immunity Are Less Critical

2004 ◽  
Vol 78 (6) ◽  
pp. 2701-2710 ◽  
Author(s):  
Sujan Shresta ◽  
Jennifer L. Kyle ◽  
Heidi M. Snider ◽  
Manasa Basavapatna ◽  
P. Robert Beatty ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Dengue Virus ◽  
B Cell ◽  
Severe Disease ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Viral Spread ◽  
Ifn Γ ◽  
Β Receptor

ABSTRACT Dengue virus (DEN) causes dengue fever and dengue hemorrhagic fever/dengue shock syndrome, which are major public health problems worldwide. The immune factors that control DEN infection or contribute to severe disease are neither well understood nor easy to examine in humans. In this study, we used wild-type and congenic mice lacking various components of the immune system to study the immune mechanisms in the response to DEN infection. Our results demonstrate that alpha/beta interferon (IFN-α/β) and IFN-γ receptors have critical, nonoverlapping functions in resolving primary DEN infection. Furthermore, we show that IFN-α/β receptor-mediated action limits initial DEN replication in extraneural sites and controls subsequent viral spread into the central nervous system (CNS). In contrast, IFN-γ receptor-mediated responses seem to act at later stages of DEN disease by restricting viral replication in the periphery and eliminating virus from the CNS. Mice deficient in B, CD4+ T, or CD8+ T cells had no increased susceptibility to DEN; however, RAG mice (deficient in both B and T cells) were partially susceptible to DEN infection. In summary, (i) IFN-α/β is critical for early immune responses to DEN infection, (ii) IFN-γ-mediated immune responses are crucial for both early and late clearance of DEN infection in mice, and (iii) the IFN system plays a more important role than T- and B-cell-dependent immunity in resistance to primary DEN infection in mice.

scholarly journals Clinical Characteristics, Histopathology, and Tissue Immunolocalization of Chikungunya Virus Antigen in Fatal Cases

2020 ◽  
Author(s):  
Tyler M Sharp ◽  
M Kelly Keating ◽  
Wun-Ju Shieh ◽  
Julu Bhatnagar ◽  
Brigid C Bollweg ◽  
...  
Keyword(s):  
Septic Shock ◽  
Chikungunya Virus ◽  
Mononuclear Cells ◽  
Virus Antigen ◽  
Chikv Infection ◽  
Illness Onset ◽  
Postmortem Blood ◽  
Tissue Specimens ◽  
Record Review ◽  
Histopathologic Findings

Abstract Background Death in patients with chikungunya is rare and has been associated with encephalitis, hemorrhage, and septic shock. We describe clinical, histologic, and immunohistochemical findings in individuals who died following chikungunya virus (CHIKV) infection. Methods We identified individuals who died in Puerto Rico during 2014 following an acute illness and had CHIKV RNA detected by reverse transcriptase–polymerase chain reaction in a pre- or postmortem blood or tissue specimen. We performed histopathology and immunohistochemistry (IHC) for CHIKV antigen on tissue specimens and collected medical data via record review and family interviews. Results Thirty CHIKV-infected fatal cases were identified (0.8/100 000 population). The median age was 61 years (range: 6 days–86 years), and 19 (63%) were male. Death occurred a median of 4 days (range: 1–29) after illness onset. Nearly all (93%) had at least 1 comorbidity, most frequently hypertension, diabetes, or obesity. Nine had severe comorbidities (eg, chronic heart or kidney disease, sickle cell anemia) or coinfection (eg, leptospirosis). Among 24 fatal cases with tissue specimens, 11 (46%) were positive by IHC. CHIKV antigen was most frequently detected in mesenchymal tissues and mononuclear cells including tissue macrophages, blood mononuclear cells, splenic follicular dendritic cells, and Kupffer cells. Common histopathologic findings were intra-alveolar hemorrhage and edema in the lung, chronic or acute tenosynovitis, and increased immunoblasts in the spleen. CHIKV infection likely caused fatal septic shock in 2 patients. Conclusions Evaluation of tissue specimens provided insights into the pathogenesis of CHIKV, which may rarely result in septic shock and other severe manifestations.

scholarly journals Pathogenesis of Dengue: Dawn of a New Era

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 1353 ◽  
Author(s):  
Scott B. Halstead
Keyword(s):  
Severe Disease ◽  
Dengue Shock Syndrome ◽  
Hemorrhagic Fever ◽  
Denv Infection ◽  
Severe Dengue ◽  
Structural Protein ◽  
New Era ◽  
Dengue Disease ◽  
Toll Receptor

Dengue virus (DENV) infections of humans were long thought to be self-limited and of low mortality. Beginning in the 1950s, at the time when four different DENVs were discovered, a lethal variant of dengue emerged. Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) initially observed in Southeast Asia now has spread throughout the world. Two risk factors for DHF/DSS are well-established: severe disease occurs during a second heterotypic DENV infection or during a first DENV infection in infants born to dengue-immune mothers. A large number of hypotheses have been proposed to explain severe dengue disease. As discussed, few of them attempt to explain why severe disease occurs under the two different immunological settings. New experimental evidence has demonstrated that DENV non-structural protein 1 (NS1) is toll-receptor 4 agonist that stimulates primary human myeloid cells to produce the same cytokines observed during the course of severe dengue disease. In addition, NS1 directly damages endothelial cells. These observations have been repeated and extended to an in vivo mouse model. The well-established phenomenon, antibody-dependent enhancement of DENV infection in Fc-receptor-bearing cells, should similarly enhance the production of DENV NS1 in humans, providing a unitary mechanism for severe disease in both immunological settings

scholarly journals A Mouse Model for Studying Post-Acute Arthritis of Chikungunya

2021 ◽  
Vol 9 (9) ◽  
pp. 1998
Author(s):  
Aileen Y. Chang ◽  
Sarah R. Tritsch ◽  
Abigail J. Porzucek ◽  
Arnold M. Schwartz ◽  
Margaux Seyler-Schmidt ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mouse Models ◽  
Targeted Therapies ◽  
Scoring System ◽  
Chikungunya Virus ◽  
Evidence Based ◽  
Novel Therapies ◽  
Wild Type ◽  
Chikv Infection ◽  
Acute Arthritis

Chikungunya virus (CHIKV) was introduced to the Americas in 2013, causing two million infections across over thirty countries. CHIKV causes a chronic debilitating arthritis in one fourth of infected individuals and currently evidence-based targeted therapies for the treatment of CHIKV arthritis are lacking. Multiple mouse models of chikungunya have been developed to study acute CHIKV infection. In humans, post-CHIKV arthritis may persist for months to years after viremia from a CHIKV infection has resolved. Therefore, the development of a mouse model of post-acute arthritis of chikungunya may facilitate the study of potential novel therapeutics for this arthritis. In this article we describe the development of a wild-type immunocompetent C57BL/6 mouse model for post-acute arthritis of chikungunya, including a histologic inflammation scoring system, as well as suggestions for how this mouse model may be used to examine the efficacy of novel therapies for CHIKV arthritis.

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