scholarly journals Liver bacterial dysbiosis occurs in SIV-infected macaques and persists during antiretroviral therapy

2020 ◽  
Author(s):  
Bridget S Fisher ◽  
Katherine A Fancher ◽  
Andrew T Gustin ◽  
Cole Fisher ◽  
Matthew P Wood ◽  
...  
Keyword(s):  
Liver Disease ◽  
Antiretroviral Therapy ◽  
Inflammatory Responses ◽  
Rhesus Macaques ◽  
Neutrophil Infiltration ◽  
Opportunistic Pathogen ◽  
Environmental Mycobacteria ◽  
Siv Infection ◽  
Abundant Genus

Abstract Background: Liver disease remains a significant contributor to morbidity and mortality in HIV-infected individuals, even during successful treatment with combination antiretroviral therapy (cART). In non-human primates, SIV infection is associated with gut microbiome dysbiosis as well as bacterial translocation into the colonic lamina propria and liver via the portal vein. Here the liver microbiome was evaluated in rhesus macaques to discern the influence of SIV infection alone (SIV+) and during cART administration (SIV+cART) on liver bacterial dysbiosis and neutrophil infiltration.Results: Dysbiosis in liver bacterial composition was observed, encompassing changes in a number of genera, during SIV infection in the absence and presence of cART. The most striking finding was an increase in the level of Mycobacterium, which while barely detectable in the uninfected macaques, was the most abundant genus observed in the livers of a majority SIV+ and SIV+cART macaques. Multi-gene sequencing analyses identified a species of environmental mycobacteria similar to the opportunistic pathogen M. smegmatis. The effect of M. smegmatis on host gene expression in primary hepatocytes was evaluated in vitro utilizing PILAM, a glycolipid cell wall component found in atypical Mycobacteria. PILAM induced an upregulation of inflammatory responses, including an increase in the chemokines associated with neutrophil chemotaxis (CXCL1, CXCL5, and CXCL6). Assessment of the macaque livers by microscopy determined that neutrophil levels were reduced in SIV+cART macaques, suggesting that the SIV infection and/or cART treatment influence the liver-associated neutrophil response. Conclusions: A number of liver bacteria genera were altered following SIV infection even in the context of cART, possibly as a consequence of reduced neutrophil recruitment. Mycobacteria became a major component of the SIV infected macaque liver microbiome, raising the possibility that bacteria of this genus might contribute to liver disease in HIV infected patients.

scholarly journals Crosstalk between Oxidative Stress and Inflammatory Liver Injury in the Pathogenesis of Alcoholic Liver Disease

2022 ◽  
Vol 23 (2) ◽  
pp. 774
Author(s):  
Yoon Mee Yang ◽  
Ye Eun Cho ◽  
Seonghwan Hwang
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Alcoholic Liver Disease ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Pathological Features ◽  
Excessive Alcohol Consumption ◽  
Excessive Alcohol ◽  
The Relationship

Alcoholic liver disease (ALD) is characterized by the injury, inflammation, and scarring in the liver owing to excessive alcohol consumption. Currently, ALD is a leading cause for liver transplantation. Therefore, extensive studies (in vitro, in experimental ALD models and in humans) are needed to elucidate pathological features and pathogenic mechanisms underlying ALD. Notably, oxidative changes in the liver have been recognized as a signature trait of ALD. Progression of ALD is linked to the generation of highly reactive free radicals by reactions involving ethanol and its metabolites. Furthermore, hepatic oxidative stress promotes tissue injury and, in turn, stimulates inflammatory responses in the liver, forming a pathological loop that promotes the progression of ALD. Accordingly, accumulating further knowledge on the relationship between oxidative stress and inflammation may help establish a viable therapeutic approach for treating ALD.

scholarly journals Intrinsic Susceptibility of Rhesus Macaque Peripheral CD4+ T Cells to Simian Immunodeficiency Virus In Vitro Is Predictive of In Vivo Viral Replication

2000 ◽  
Vol 74 (20) ◽  
pp. 9388-9395 ◽  
Author(s):  
Simoy Goldstein ◽  
Charles R. Brown ◽  
Houman Dehghani ◽  
Jeffrey D. Lifson ◽  
Vanessa M. Hirsch
Keyword(s):  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Rank Order ◽  
Rhesus Macaques ◽  
Target Cells ◽  
Plasma Viremia ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACT Previous studies with simian immunodeficiency virus (SIV) infection of rhesus macaques suggested that the intrinsic susceptibility of peripheral blood mononuclear cells (PBMC) to infection with SIV in vitro was predictive of relative viremia after SIV challenge. The present study was conducted to evaluate this parameter in a well-characterized cohort of six rhesus macaques selected for marked differences in susceptibility to SIV infection in vitro. Rank order relative susceptibility of PBMC to SIVsmE543-3-infection in vitro was maintained over a 1-year period of evaluation. Differential susceptibility of different donors was maintained in CD8+T-cell-depleted PBMC, macrophages, and CD4+ T-cell lines derived by transformation of PBMC with herpesvirus saimiri, suggesting that this phenomenon is an intrinsic property of CD4+target cells. Following intravenous infection of these macaques with SIVsmE543-3, we observed a wide range in plasma viremia which followed the same rank order as the relative susceptibility established by in vitro studies. A significant correlation was observed between plasma viremia at 2 and 8 weeks postinoculation and in vitro susceptibility (P < 0.05). The observation that the two most susceptible macaques were seropositive for simian T-lymphotropic virus type 1 may suggests a role for this viral infection in enhancing susceptibility to SIV infection in vitro and in vivo. In summary, intrinsic susceptibility of CD4+ target cells appears to be an important factor influencing early virus replication patterns in vivo that should be considered in the design and interpretation of vaccine studies using the SIV/macaque model.

scholarly journals Plasmacytoid dendritic cells are recruited to the colorectum and contribute to immune activation during pathogenic SIV infection in rhesus macaques

Blood ◽  
2011 ◽  
Vol 118 (10) ◽  
pp. 2763-2773 ◽  
Author(s):  
Suefen Kwa ◽  
Sunil Kannanganat ◽  
Pragati Nigam ◽  
Mariam Siddiqui ◽  
Ravi Dyavar Shetty ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Activation ◽  
Rhesus Macaques ◽  
Virus Infections ◽  
Natural Hosts ◽  
Siv Infection ◽  
Gastrointestinal Tissue ◽  
The Impact

AbstractIn SIV/HIV infection, the gastrointestinal tissue dominates as an important site because of the impact of massive mucosal CD4 depletion and immune activation-induced tissue pathology. Unlike AIDS-susceptible rhesus macaques, natural hosts do not progress to AIDS and resolve immune activation earlier. Here, we examine the role of dendritic cells (DCs) in mediating immune activation and disease progression. We demonstrate that plasmacytoid DCs (pDCs) in the blood up-regulate β7-integrin and are rapidly recruited to the colorectum after a pathogenic SIV infection in rhesus macaques. These pDCs were capable of producing proinflammatory cytokines and primed a T cytotoxic 1 response in vitro. Consistent with the up-regulation of β7-integrin on pDCs, in vivo blockade of α4β7-integrin dampened pDC recruitment to the colorectum and resulted in reduced immune activation. The up-regulation of β7-integrin expression on pDCs in the blood also was observed in HIV-infected humans but not in chronically SIV-infected sooty mangabeys that show low levels of immune activation. Our results uncover a new mechanism by which pDCs influence immune activation in colorectal tissue after pathogenic immunodeficiency virus infections.

scholarly journals Modulation of Immune Complex–induced Inflammation In Vivo by the Coordinate Expression of Activation and Inhibitory Fc Receptors

1999 ◽  
Vol 189 (1) ◽  
pp. 179-186 ◽  
Author(s):  
Raphael Clynes ◽  
Jay S. Maizes ◽  
Rodolphe Guinamard ◽  
Masao Ono ◽  
Toshiyuki Takai ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Immune Complexes ◽  
Inflammatory Responses ◽  
Fc Receptors ◽  
Inflammatory Cells ◽  
Neutrophil Infiltration ◽  
Calcium Flux ◽  
Deficient Mice

Autoantibodies and immune complexes are major pathogenic factors in autoimmune injury, responsible for initiation of the inflammatory cascade and its resulting tissue damage. This activation results from the interaction of immunoglobulin (Ig)G Fc receptors containing an activation motif (ITAM) with immune complexes (ICs) and cytotoxic autoantibodies which initiates and propagates an inflammatory response. In vitro, this pathway can be interrupted by coligation to FcγRIIB, an IgG Fc receptor containing an inhibitory motif (ITIM). In this report, we describe the in vivo consequences of FcγRII deficiency in the inflammatory response using a mouse model of IC alveolitis. At subthreshold concentrations of ICs that fail to elicit inflammatory responses in wild-type mice, FcγRII-deficient mice developed robust inflammatory responses characterized by increased hemorrhage, edema, and neutrophil infiltration. Bronchoalveolar fluids from FcγRII−/− stimulated mice contain higher levels of tumor necrosis factor and chemotactic activity, suggesting that FcγRII deficiency lowers the threshold of IC stimulation of resident cells such as the alveolar macrophage. In contrast, complement- and complement receptor–deficient mice develop normal inflammatory responses to suprathreshold levels of ICs, while FcRγ−/− mice are completely protected from inflammatory injury. An inhibitory role for FcγRII on macrophages is demonstrated by analysis of FcγRII−/− macrophages which show greater phagocytic and calcium flux responses upon FcγRIII engagement. These data reveal contrasting roles for the cellular receptors for IgG on inflammatory cells, providing a regulatory mechanism for setting thresholds for IC sensitivity based on the ratio of ITIM to ITAM FcγR expression. Exploiting the FcγRII inhibitory pathway could thus provide a new therapeutic approach for modulating antibody-triggered inflammation.

scholarly journals Alterations of the gut bacterial microbiota in rhesus macaques with SIV infection and on short- or long-term antiretroviral therapy

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Summer Siddiqui ◽  
Duran Bao ◽  
Lara Doyle-Meyers ◽  
Jason Dufour ◽  
Yuntao Wu ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Gut Microbiota ◽  
Immune Activation ◽  
Rhesus Macaques ◽  
Microbial Translocation ◽  
Time Points ◽  
Siv Infection ◽  
The Impact ◽  
Hiv 1

Abstract Gut dysbiosis and microbial translocation are associated with chronic systemic immune activation and inflammation in HIV-1 infection. However, the extent of restoration of gut microbiota in HIV-1 patients with short or long-term antiretroviral therapy (ART) is unclear. To understand the impact of ART on the gut microbiota, we used the rhesus macaque model of SIV infection to characterize and compare the gut microbial community upon SIV infection and during ART. We observed altered taxonomic compositions of gut microbiota communities upon SIV infection and at different time points of ART. SIV-infected animals showed decreased diversity of gut microbiome composition, while the ART group appeared to recover towards the diversity level of the healthy control. Animals undergoing ART for various lengths of time were observed to have differential gut bacterial abundance across different time points. In addition, increased blood lipopolysaccharide (LPS) levels during SIV infection were reduced to near normal upon ART, indicating that microbial translocation and immune activation can be improved during therapy. In conclusion, while short ART may be related to transient increase of certain pathogenic bacterial microbiome, ART may promote microbiome diversity compromised by SIV infection, improve the gut microbiota towards the healthy compositions and alleviate immune activation.

scholarly journals The Impact of Acute or Chronic Alcohol Intake on the NF-κB Signaling Pathway in Alcohol-Related Liver Disease

2020 ◽  
Vol 21 (24) ◽  
pp. 9407
Author(s):  
Aleksander J. Nowak ◽  
Borna Relja
Keyword(s):  
Liver Disease ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
In Vivo Studies ◽  
Related Liver Disease ◽  
The Impact

Ethanol misuse is frequently associated with a multitude of profound medical conditions, contributing to health-, individual- and social-related damage. A particularly dangerous threat from this classification is coined as alcoholic liver disease (ALD), a liver condition caused by prolonged alcohol overconsumption, involving several pathological stages induced by alcohol metabolic byproducts and sustained cellular intoxication. Molecular, pathological mechanisms of ALD principally root in the innate immunity system and are especially associated with enhanced functionality of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. NF-κB is an interesting and convoluted DNA transcription regulator, promoting both anti-inflammatory and pro-inflammatory gene expression. Thus, the abundancy of studies in recent years underlines the importance of NF-κB in inflammatory responses and the mechanistic stimulation of inner molecular motifs within the factor components. Hereby, in the following review, we would like to put emphasis on the correlation between the NF-κB inflammation signaling pathway and ALD progression. We will provide the reader with the current knowledge regarding the chronic and acute alcohol consumption patterns, the molecular mechanisms of ALD development, the involvement of the NF-κB pathway and its enzymatic regulators. Therefore, we review various experimental in vitro and in vivo studies regarding the research on ALD, including the recent active compound treatments and the genetic modification approach. Furthermore, our investigation covers a few human studies.

Antiretroviral therapy attenuates dysregulated hematopoiesis caused by chronic binge alcohol and SIV infection in rhesus macaques

Alcohol ◽  
2014 ◽  
Vol 48 (7) ◽  
pp. 730
Author(s):  
L.W. Li ◽  
G.J. Bagby ◽  
S. Nelson ◽  
P.E. Molina ◽  
D.A. Welsh ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Rhesus Macaques ◽  
Siv Infection

scholarly journals Reduced Simian Immunodeficiency Virus Replication in Macrophages of Sooty Mangabeys Is Associated with Increased Expression of Host Restriction Factors

2015 ◽  
Vol 89 (20) ◽  
pp. 10136-10144 ◽  
Author(s):  
Kiran D. Mir ◽  
Maud Mavigner ◽  
Charlene Wang ◽  
Mirko Paiardini ◽  
Donald L. Sodora ◽  
...  
Keyword(s):  
Rhesus Macaques ◽  
Primate Species ◽  
Restriction Factors ◽  
Macrophage Infection ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Sooty Mangabeys ◽  
Siv Infection

ABSTRACTMacrophages are target cells of HIV/SIV infection that may play a role in AIDS pathogenesis and contribute to the long-lived reservoir of latently infected cells during antiretroviral therapy (ART). In previous work, we and others have shown that during pathogenic SIV infection of rhesus macaques (RMs), rapid disease progression is associated with high levels ofin vivomacrophage infection. In contrast, during nonpathogenic SIV infection of sooty mangabeys (SMs), neither spontaneous nor experimental CD4+T cell depletion results in substantial levels ofin vivomacrophage infection. To test the hypothesis that SM macrophages are intrinsically more resistant to SIV infection than RM macrophages, we undertook anin vitrocomparative assessment of monocyte-derived macrophages (MDMs) from both nonhuman primate species. Using the primary isolate SIVM949, which replicates well in lymphocytes from both RMs and SMs, we found that infection of RM macrophages resulted in persistent SIV-RNA production while SIV-RNA levels in SM macrophage cultures decreased 10- to 100-fold over a similar temporal course ofin vitroinfection. To explore potential mechanisms responsible for the lower levels of SIV replication and/or production in macrophages from SMs we comparatively assessed, in the two studied species, the expression of the SIV coreceptor as well as the expression of a number of host restriction factors. While previous studies showed that SM monocytes express lower levels of CCR5 (but not CD4) than RM monocytes, the level of CCR5 expression in MDMs was similar in the two species. Interestingly, we found that SM macrophages exhibited a significantly greater increase in the expression of tetherin (P= 0.003) and TRIM22 (P= 0.0006) in response to alpha interferon stimulation and increased expression of multiple host restriction factors in response to lipopolysaccharide stimulation and exposure to SIV. Overall, these findings confirm, in anin vitroinfection system, that SM macrophages are relatively more resistant to SIV infection compared to RM macrophages, and suggest that a combination of entry and postentry restriction mechanisms may protect these cells from productive SIV infection.IMPORTANCEThis manuscript represents the firstin vivocomparative analysis of monocyte-derived macrophages (MDMs) between rhesus macaques, i.e., experimental SIV hosts in which the infection is pathogenic and macrophages can be infected, and sooty mangabeys, i.e., natural SIV hosts in which the infection is nonpathogenic and macrophages are virtually never infectedin vivo. This study demonstrates that mangabey-derived MDMs are more resistant to SIV infectionin vitrocompared to macaque-derived MDMs, and provides a potential explanation for this observation by showing increased expression of specific retrovirus restriction factors in mangabey-derived macrophages. Overall, this study is important as it contributes to our understanding of why SIV infection is nonpathogenic in sooty mangabeys while it is pathogenic in macaques, and is consistent with a pathogenic role forin vivomacrophage infection during pathogenic lentiviral infection.

scholarly journals Liver Bacterial Dysbiosis With Non-Tuberculosis Mycobacteria Occurs in SIV-Infected Macaques and Persists During Antiretroviral Therapy

2022 ◽  
Vol 12 ◽  
Author(s):  
Bridget S. Fisher ◽  
Katherine A. Fancher ◽  
Andrew T. Gustin ◽  
Cole Fisher ◽  
Matthew P. Wood ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Relative Abundance ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Phosphatidyl Inositol ◽  
Opportunistic Pathogen ◽  
Atypical Mycobacteria ◽  
Microbial Composition ◽  
Transcriptional Responses ◽  
Pass Through

Liver disease is a significant contributor to morbidity and mortality in HIV-infected individuals, even during successful viral suppression with combination antiretroviral therapy (cART). Similar to HIV infection, SIV infection of rhesus macaques is associated with gut microbiome dysbiosis and microbial translocation that can be detected systemically in the blood. As microbes leaving the intestines must first pass through the liver via the portal vein, we evaluated the livers of both SIV-infected (SIV+) and SIV-infected cART treated (SIV+cART) rhesus macaques for evidence of microbial changes compared to uninfected macaques. Dysbiosis was observed in both the SIV+ and SIV+cART macaques, encompassing changes in the relative abundance of several genera, including a reduction in the levels of Lactobacillus and Staphylococcus. Most strikingly, we found an increase in the relative abundance and absolute quantity of bacteria within the Mycobacterium genus in both SIV+ and SIV+cART macaques. Multi-gene sequencing identified a species of atypical mycobacteria similar to the opportunistic pathogen M. smegmatis. Phosphatidyl inositol lipoarabinomannan (PILAM) (a glycolipid cell wall component found in atypical mycobacteria) stimulation in primary human hepatocytes resulted in an upregulation of inflammatory transcriptional responses, including an increase in the chemokines associated with neutrophil recruitment (CXCL1, CXCL5, and CXCL6). These studies provide key insights into SIV associated changes in hepatic microbial composition and indicate a link between microbial components and immune cell recruitment in SIV+ and SIV+cART treated macaques.

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