scholarly journals Germ-Free Conditions Modulate Host Purine Metabolism, Exacerbating Adenine-Induced Kidney Damage

Toxins ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 547
Author(s):  
Eikan Mishima ◽  
Mariko Ichijo ◽  
Takeshi Kawabe ◽  
Koichi Kikuchi ◽  
Yukako Akiyama ◽  
...  
Keyword(s):  
Immune Responses ◽  
Purine Metabolism ◽  
Kidney Damage ◽  
Metabolome Analysis ◽  
Metabolizing Enzymes ◽  
Germ Free ◽  
Disease Condition ◽  
Purine Metabolite ◽  
Deficient Mice

Alterations in microbiota are known to affect kidney disease conditions. We have previously shown that germ-free conditions exacerbated adenine-induced kidney damage in mice; however, the mechanism by which this occurs has not been elucidated. To explore this mechanism, we examined the influence of germ-free conditions on purine metabolism and renal immune responses involved in the kidney damage. Germ-free mice showed higher expression levels of purine-metabolizing enzymes such as xanthine dehydrogenase, which converts adenine to a nephrotoxic byproduct 2,8-dihydroxyadenine (2,8-DHA). The germ-free mice also showed increased urinary excretion of allantoin, indicating enhanced purine metabolism. Metabolome analysis demonstrated marked differences in the purine metabolite levels in the feces of germ-free mice and mice with microbiota. Furthermore, unlike the germ-free condition, antibiotic treatment did not increase the expression of purine-metabolizing enzymes or exacerbate adenine-induced kidney damage. Considering renal immune responses, the germ-free mice displayed an absence of renal IL-17A expression. However, the adenine-induced kidney damage in wild-type mice was comparable to that in IL-17A-deficient mice, suggesting that IL-17A does not play a major role in the disease condition. Our results suggest that the enhanced host purine metabolism in the germ-free mice potentially promotes the conversion of the administered adenine into 2,8-DHA, resulting in exacerbated kidney damage. This further suggests a role of the microbiota in regulating host purine metabolism.

Abstract 116: Detrimental Role of Toll-Like Receptor 4 in Cardiovirus-Induced Myocarditis

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Fumitaka Sato ◽  
Seiichi Omura ◽  
Nicholas E Martinez ◽  
Eiichiro Kawai ◽  
Ganta V Chaitanya ◽  
...  
Keyword(s):  
Immune Responses ◽  
Acute Phase ◽  
Viral Entry ◽  
Viral Myocarditis ◽  
Chronic Phase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tlr4 Ligand ◽  
Ifn Γ ◽  
Deficient Mice

Picornavirus infections have been known as a leading cause of viral myocarditis in humans. Theiler’s murine encephalomyelitis virus (TMEV) belongs to the genus Cardiovirus, the family Picornaviridae and was reported to cause inflammation in the heart in one manuscript, while its pathomechanism is unclear. In viral myocarditis, viral replication in the heart and/or immune responses against virus as well as heart-antigen (autoimmunity) can contribute to the pathogenesis. Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) that are important for recognizing pathogens as well as triggering innate immunity. Among TLRs, TLR4 has been demonstrated to play important roles in virus-mediated pathology: 1) TLR4 can contribute to viral entry in some viruses, 2) TLR4 may mediate tissue damage by anti-virus immune responses (immunopathology), 3) high levels of TLR4 expression were observed in the heart of patients with dilated cardiomyopathy following acute viral myocarditis, and 4) some viruses can bind to lipopolysaccharide (LPS), which is a TLR4 ligand. To determine the role of TLR4 in TMEV-induced myocarditis, we infected male C3H/HeJ (TLR4-deficient) and C3H/HeNtac (control TLR4+) mice with the DA strain of TMEV. We harvested the hearts and spleens on days 6 and 7 (acute phase) or days 63 and 64 (chronic phase) post-infection. Cardiac pathology was evaluated by hematoxylin and eosin staining and production of pro-inflammatory cytokines, interleukin (IL)-17A and interferon (IFN)-γ, from spleen cells was measured by an enzyme-linked immunosorbent assay (ELISA). In both mice, mild myocarditis was observed during the acute phase of TMEV infection. During the chronic phase, both mice developed severe pathology in the heart, including basophilic degeneration and calcification. However, the incidence of myocarditis was higher in control mice than TLR4-deficient mice. IL-17A and IFN-γ production was higher in control mice than in TLR4-deficient mice (control vs. TLR4-deficient mice, acute phase: IL-17A, 196 vs. 146 pg/ml; IFN-γ, 72 vs. 39 ng/ml; chronic phase: IL-17A, 290 vs. 229 pg/ml; IFN- γ, 142 vs. 88 ng/ml). These results suggest that TLR4 may be detrimental in TMEV-induced myocarditis by increasing pro-inflammatory cytokine production.

scholarly journals The microbiota plays a critical role in the reactivity of lung immune components to innate ligands

2020 ◽  
Author(s):  
Quentin Marquant ◽  
Daphné Laubreton ◽  
Carole Drajac ◽  
Elliot Mathieu ◽  
Edwige Bouguyon ◽  
...  
Keyword(s):  
Immune Responses ◽  
Critical Role ◽  
Innate Immune ◽  
Immune Reactivity ◽  
Innate Immune Responses ◽  
Plain Language ◽  
Pulmonary Tissue ◽  
Germ Free ◽  
Syncytial Virus

AbstractThe microbiota contributes to shaping efficient and safe immune defenses in the gut. However, little is known about the role of the microbiota in the education of pulmonary innate immune responses. Here, we tested whether the endogenous microbiota can modulate reactivity of pulmonary tissue to pathogen stimuli by comparing the response of specific pathogen-free (SPF) and germ-free (GF) mice. Using SPF and GF mice intranasally exposed to lipopolysaccharide (LPS), a component of Gram-negative bacteria, we observed earlier and greater inflammation in the pulmonary compartment of GF mice than that of SPF mice. Toll-like receptor 4 (TLR4) was more abundantly expressed in the lungs of GF mice than those of SPF mice at steady state, which could predispose the innate immunity of GF mice to strongly react to environmental stimuli. Lung explants were stimulated with different TLR agonists or infected with the human airways pathogen, respiratory syncytial virus (RSV), resulting in greater inflammation under almost all conditions for the GF explants. Finally, alveolar macrophages (AM) from GF mice presented a higher innate immune response upon RSV infection than those of SPF mice. Overall, these data suggest that the presence of microbiota in SPF mice induced a process of innate immune tolerance in the lungs by a mechanism which remains to be elucidated. Our study represents a step forward to establishing the link between the microbiota and the immune reactivity of the lungs.Plain Language summaryMicrobiota represents an important partner of immunologic system at the interface between immune cells and epithelium. It is well known, notably in the gut, that the microbiota contributes in shaping efficient and safe defenses. However, little is known about the role of the microbiota in the education of pulmonary innate immune responses. In this study, we postulate that endogenous microbiota could dampen an excessive reactivity of pulmonary tissue to external stimuli. Thus, we sought to study the innate immune reaction switched on by viral or bacterial ligands in respiratory tract cells coming from mice with or without microbiota (germ-free condition, GF). Altogether, our results show a higher inflammatory reaction in GF condition. This study represents a step forward to better establish the link between the microbiota and the reactivity of the lung tissue. Not only these data demonstrate that the microbiota educates the pulmonary innate immune system, but also contributes the emerging concept of using respiratory commensal bacteria as potential next-generation probiotics to prevent susceptibility to respiratory diseases.

scholarly journals The Role of Vitamin D and Vitamin D Receptor in Immunity toLeishmania majorInfection

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
James P. Whitcomb ◽  
Mary DeAgostino ◽  
Mark Ballentine ◽  
Jun Fu ◽  
Martin Tenniswood ◽  
...  
Keyword(s):  
Vitamin D ◽  
Immune Responses ◽  
Vitamin D Receptor ◽  
Leishmania Major ◽  
Active Form ◽  
Wild Type ◽  
Vitamin D Signaling ◽  
Deficient Mice ◽  
Th 1

Vitamin D signaling modulates a variety of immune responses. Here, we assessed the role of vitamin D in immunity to experimental leishmaniasis infection in vitamin D receptor-deficient mice (VDRKO). We observed that VDRKO mice on a genetically resistant background have decreasedLeishmania major-induced lesion development compared to wild-type (WT) mice; additionally, parasite loads in infected dermis were significantly lower at the height of infection. Enzymatic depletion of the active form of vitamin D mimics the ablation of VDR resulting in an increased resistance toL. major. Conversely, VDRKO or vitamin D-deficient mice on the susceptible Th2-biased background had no change in susceptibility. These studies indicate vitamin D deficiency, either through the ablation of VDR or elimination of its ligand, 1,25D3, leads to an increase resistance toL. majorinfection but only in a host that is predisposed for Th-1 immune responses.

scholarly journals The role of IL-5, IL-6 and IL-10 in primary and vaccine-primed immune responses to infection with Friend retrovirus (Murine leukaemia virus)

2001 ◽  
Vol 82 (6) ◽  
pp. 1349-1354 ◽  
Author(s):  
Beatrice D. Strestik ◽  
Anke R. M. Olbrich ◽  
Kim J. Hasenkrug ◽  
Ulf Dittmer
Keyword(s):  
Immune Responses ◽  
Viral Infections ◽  
Vaccine Virus ◽  
Live Attenuated Vaccine ◽  
Leukaemia Virus ◽  
Murine Leukaemia Virus ◽  
Friend Retrovirus ◽  
Suppressive Cytokine ◽  
Deficient Mice

The defence of a host against viral infections is strongly influenced by cytokines. We investigated the role of the B-cell stimulating cytokines IL-5 and IL-6, and the immuno-suppressive cytokine IL-10, during primary and secondary immune responses in mice against infection with Friend retrovirus (FV) (Murine leukaemia virus). IL-5−/− mice were comparable to C57BL/6 wild-type mice in their ability to control acute FV infection. In contrast, IL-6−/− and IL-10−/− mice showed significantly enhanced virus loads in spleen cells. However, this impaired control of acute FV replication did not alter the long-term control over persistent FV in IL-6−/− and IL-10−/− mice. Immunization with a live attenuated vaccine virus prior to challenge protected all three types of cytokine-deficient mice from high levels of spleen virus, despite the finding that the vaccinated IL-5- and IL-6-deficient mice had significantly reduced titres of virus-neutralizing IgG class antibodies. The results indicate that IL-6 and IL-10 contribute to primary immune responses against FV, but are dispensable during persistent infection and vaccine-primed secondary responses.

Abstract O.24: Gut Microflora Influences Pathology in the Kawasaki Disease Vasculitis Mouse Model

Circulation ◽  
2015 ◽  
Vol 131 (suppl_2) ◽  
Author(s):  
Daiko Wakita ◽  
Yosuke Kurashima ◽  
Yoshihiro Takasato ◽  
Youngho Lee ◽  
Kenichi Shimada ◽  
...  
Keyword(s):  
Cell Wall ◽  
Kawasaki Disease ◽  
Mouse Model ◽  
Immune Responses ◽  
Critical Role ◽  
Gut Microflora ◽  
Vascular Abnormalities ◽  
Coronary Arteritis ◽  
Deficient Mice

Background: Kawasaki Disease (KD) is the leading cause of acquired heart disease in the US. We have demonstrated the critical role of innate immune responses via IL-1R/MyD88 signaling in the Lactobacillus casei cell wall extract (LCWE)-induced KD mouse model. The diversity and composition of microflora (both bacterial and fungal) have been associated with the regulation and alterations of immune responses and various pathologies. However, the role of gut microbiota in immunopathology of KD has not been investigated. Objective: To evaluate the role of gut microflora in development of coronary arteritis, and vascular abnormalities in KD mouse model. Methods and Results: We investigated the role of gut microflora in the LCWE-induced KD mouse model, using Specific-Pathogen Free (SPF) and Germ Free (GF) mice (C57BL/6). GF mice showed a significant decrease of KD lesions, including coronary arteritis compared with SPF mice. The development of LCWE-induced AAA, which we recently discovered in this mouse model, was also markedly diminished in GF mice. In addition to GF mice, we also investigated the specific role of commensal fungi, and determined whether altered fungal burden in this KD mouse model contributes to disease severity. To deplete fungi in the gut microflora, we exposed pregnant SPF mice and their offspring to fluconazole (antifungal) in their drinking water for 5 wks and induced KD. The fluconazole treated mice had significantly reduced coronary arteritis, and AAA compared to controls. Since Dectin-1 has emerged as a key receptor that recognizes β-1,3-glucans found in the cell wall of nearly all fungi, we next induced KD in Dectin-1 deficient mice. Dectin-1 deficient mice also had significantly reduced KD lesions such as coronary arteritis compared with WT mice. Conclusions: We demonstrate here that gut microflora play a critical role in the development of KD vasculitis in LCWE-induced mouse model. Our results suggest that fungi in the intestinal microbiota may specifically control the induction and severity of KD vasculitis, which may be mediated by Dectin-1. These findings provide a new perspective on the potential role of the microbiome in KD pathogenesis and may offer new diagnostic and therapeutic strategies for KD patients.

scholarly journals IL-10-producing B cells regulate Th1/Th17-cell immune responses inPneumocystispneumonia

2019 ◽  
Vol 316 (1) ◽  
pp. L291-L301 ◽  
Author(s):  
Heng-Mo Rong ◽  
Ting Li ◽  
Chao Zhang ◽  
Dong Wang ◽  
Yang Hu ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Th17 Cell ◽  
Pneumocystis Pneumonia ◽  
Vital Role ◽  
Specific Igg ◽  
Pneumocystis Infection ◽  
Deficient Mice

Pneumocystis pneumonia (PCP) is a common opportunistic infectious disease that is prevalent in immunosuppressed hosts. Accumulating evidence shows that B cells play an important role in infectious diseases. In the present study, the immune regulatory role of mature B cells in host defense to Pneumocystis was evaluated. Pneumocystis infection resulted in a decrease in B cells in patients and mice, and the Pneumocystis burden in B cell-deficient mice also progressively increased from weeks 1 to 7 after infection. The clearance of Pneumocystis was delayed in B cell-activating factor receptor (BAFF-R)-deficient mice (BAFF-R−/−mice), which had few B cells and Pneumocystis-specific IgG and IgM antibodies, compared with clearance in wild-type (WT) mice. There were fewer effector CD4+T cells and higher percentages of T helper (Th)1/Th17 cells in BAFF-R−/−mice than in WT mice. Adoptive transfer of naive B cells, mRNA sequencing, and IL-1β neutralization experiments indicated that IL-1β is a likely determinant of the IL-10-producing B cell-mediated suppression of Th1/Th17-cell immune responses in BAFF-R−/−PCP mice. Our data indicated that B cells play a vital role in the regulation of Th cells in response to Pneumocystis infection.

scholarly journals Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity

2008 ◽  
Vol 205 (9) ◽  
pp. 2151-2162 ◽  
Author(s):  
Stefan F. Martin ◽  
Jan C. Dudda ◽  
Eva Bachtanian ◽  
Annalisa Lembo ◽  
Stefanie Liller ◽  
...  
Keyword(s):  
T Cell ◽  
Potential Role ◽  
Fluorescein Isothiocyanate ◽  
T Cell Response ◽  
Contact Hypersensitivity ◽  
Germ Free ◽  
Skin Flora ◽  
Allergic Contact ◽  
Deficient Mice

Allergic contact hypersensitivity (CHS) is a T cell–mediated inflammatory skin disease. Interleukin (IL)-12 is considered to be important in the generation of the allergen-specific T cell response. Loss of IL-12 function in IL-12Rβ2–deficient mice, however, did not ameliorate the allergic immune response, suggesting alternate IL-12–independent pathways in the induction of CHS. Because exposure to contact allergens always takes place in the presence of microbial skin flora, we investigated the potential role of Toll-like receptors (TLRs) in the induction of CHS. Using mice deficient in TLR4, the receptor for bacterial lipopolysaccharide (LPS), IL-12 receptor (R) β2, or both, we show that the concomitant absence of TLR4 and IL-12Rβ2, but not the absence of TLR4 or IL-12Rβ2 alone, prevented DC-mediated sensitization, generation of effector T cells, and the subsequent CHS response to 2,4,6-trinitro-1-chlorobenzene (TNCB), oxazolone, and fluorescein isothiocyanate. Introduction of the TLR4 transgene into the TLR4/IL-12Rβ2 mutant restored the CHS inducibility, showing a requirement for TLR4 in IL-12–independent CHS induction. Furthermore, the concomitant absence of TLR2 and TLR4 prevented the induction of CHS to TNCB in IL-12–competent mice. Finally, CHS was inducible in germ-free wild-type and IL-12Rβ2–deficient mice, but not in germ-free TLR4/IL-12Rβ2 double deficient mice, suggesting that the necessary TLR activation may proceed via endogenous ligands.

scholarly journals Commensal pathogen competition impacts host viability

2018 ◽  
Vol 115 (27) ◽  
pp. 7099-7104 ◽  
Author(s):  
David Fast ◽  
Benjamin Kostiuk ◽  
Edan Foley ◽  
Stefan Pukatzki
Keyword(s):  
Immune Responses ◽  
Regulatory Networks ◽  
Secretion System ◽  
Commensal Bacteria ◽  
Gram Negative ◽  
Acetobacter Pasteurianus ◽  
Germ Free ◽  
Host Immune Responses

While the structure and regulatory networks that govern type-six secretion system (T6SS) activity of Vibrio cholerae are becoming increasingly clear, we know less about the role of T6SS in disease. Under laboratory conditions, V. cholerae uses T6SS to outcompete many Gram-negative species, including other V. cholerae strains and human commensal bacteria. However, the role of these interactions has not been resolved in an in vivo setting. We used the Drosophila melanogaster model of cholera to define the contribution of T6SS to V. cholerae pathogenesis. Here, we demonstrate that interactions between T6SS and host commensals impact pathogenesis. Inactivation of T6SS, or removal of commensal bacteria, attenuates disease severity. Reintroduction of the commensal, Acetobacter pasteurianus, into a germ-free host is sufficient to restore T6SS-dependent pathogenesis in which T6SS and host immune responses regulate viability. Together, our data demonstrate that T6SS acts on commensal bacteria to promote the pathogenesis of V. cholerae.

scholarly journals Role of Interleukin-4 (IL-4), IL-12, and Gamma Interferon in Primary and Vaccine-Primed Immune Responses to Friend Retrovirus Infection

2001 ◽  
Vol 75 (2) ◽  
pp. 654-660 ◽  
Author(s):  
Ulf Dittmer ◽  
Karin E. Peterson ◽  
Ron Messer ◽  
Ingunn M. Stromnes ◽  
Brent Race ◽  
...  
Keyword(s):  
Immune Responses ◽  
Gamma Interferon ◽  
Immunoglobulin M ◽  
Friend Virus ◽  
T Helper ◽  
Friend Retrovirus ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Helper Type

ABSTRACT The immunological resistance of a host to viral infections may be strongly influenced by cytokines such as interleukin-12 (IL-12) and gamma interferon (IFN-γ), which promote T helper type 1 responses, and IL-4, which promotes T helper type 2 responses. We studied the role of these cytokines during primary and secondary immune responses against Friend retrovirus infections in mice. IL-4- and IL-12-deficient mice were comparable to wild-type B6 mice in the ability to control acute and persistent Friend virus infections. In contrast, more than one-third of the IFN-γ-deficient mice were unable to maintain long-term control of Friend virus and developed gross splenomegaly with high virus loads. Immunization with a live attenuated vaccine virus prior to challenge protected all three types of cytokine-deficient mice from viremia and high levels of spleen virus despite the finding that the vaccinated IFN-γ-deficient mice were unable to class switch from immunoglobulin M (IgM) to IgG virus-neutralizing antibodies. The results indicate that IFN-γ plays an important role during primary immune responses against Friend virus but is dispensable during vaccine-primed secondary responses.

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