scholarly journals An Exaggerated Immune Response in Female BALB/c Mice Controls Initial Toxoplasma gondii Multiplication but Increases Mortality and Morbidity Relative to Male Mice

Pathogens ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1154
Author(s):  
Rasha Alonaizan ◽  
Stuart Woods ◽  
Kerrie E Hargrave ◽  
Craig W. Roberts
Keyword(s):  
Immune Response ◽  
Imaging System ◽  
Acute Infection ◽  
Mortality Rates ◽  
Dependent Manner ◽  
Male Mice ◽  
Female Mice ◽  
Parasite Multiplication ◽  
Parasite Replication

Studies indicate that female mice are more susceptible to T. gondii infection, as defined by higher mortality rates in comparison to male mice. However, whether this is due to an inability to control initial parasite multiplication or due to detrimental effects of the immune system has not been determined. Therefore, the following studies were undertaken to determine the influence of sex on early parasite multiplication and the immune response during T. gondii infection and to correlate this with disease outcome. Early parasite replication was studied through applying an in vivo imaging system (IVIS) with luciferase expressing T. gondii. In parallel immunological events were studied by cytometric bead array to quantify key immunological mediators. The results confirmed the previous findings that female mice are more susceptible to acute infection, as determined by higher mortality rates and weight loss compared with males. However, conflicting with expectations, female mice had lower parasite burdens during the acute infection than male mice. Female mice also exhibited significantly increased production of Monocyte Chemoattractant Protein-1 (MCP-1), Interferon (IFN)-γ, and Tumour Necrosis Factor (TNF)-α than male mice. MCP-1 was found to be induced by T. gondii in a dose dependent manner suggesting that the observed increased levels detected in female mice was due to a host-mediated sex difference rather than due to parasite load. However, MCP-1 was not affected by physiological concentration of estrogen or testosterone, indicating that MCP-1 differences observed between the sexes in vivo are due to an as yet unidentified intermediary factor that in turn influences MCP-1 levels. These results suggest that a stronger immune response in female mice compared with male mice enhances their ability to control parasite replication but increases their morbidity and mortality.

scholarly journals Gender difference in the glucagon response to glucopenic stress in mice

2002 ◽  
Vol 282 (1) ◽  
pp. R281-R288 ◽  
Author(s):  
Sven Karlsson ◽  
Anton J. W. Scheurink ◽  
Bo Ahrén
Keyword(s):  
Gender Difference ◽  
Cell Mass ◽  
Plasma Catecholamine ◽  
Plasma Glucagon ◽  
Male Mice ◽  
Female Mice ◽  
Autonomic Activation ◽  
Catecholamine Response ◽  
Increased Sensitivity

A gender difference in the glucagon response to insulin-induced hypoglycemia was previously demonstrated in humans. Whether this reflects a gender difference in autonomic activation or in pancreatic α-cell regulation is not known. We investigated the glucagon, epinephrine, and norepinephrine responses to neuroglycopenic stress induced by 2-deoxy-d-glucose (2-DG) or insulin in female and male mice. 2-DG increased plasma glucagon levels by 559 ± 68% in females versus 281 ± 46% in males ( P< 0.01). Plasma levels of epinephrine or norepinephrine after 2-DG administration did not differ between genders. During insulin-induced hypoglycemia, the glucagon response was similarly higher in females ( P < 0.001), whereas the plasma catecholamine response was higher in males ( P < 0.05). In vivo, the glucagon response to carbachol or clonidine was higher in females ( P < 0.05). In isolated islets, the glucagon response to carbachol (100 μM; P = 0.003) but not to clonidine (1 μM) was larger in females. We conclude that in addition to a larger α-cell mass (previously described in female mice), an increased sensitivity of the glucagon-producing α-cell to cholinergic activation contributes to the larger glucagon response to glucopenic stress in female mice.

scholarly journals Deletion of the Mycobacterium tuberculosis Resuscitation-Promoting Factor Rv1009 Gene Results in Delayed Reactivation from Chronic Tuberculosis

2006 ◽  
Vol 74 (5) ◽  
pp. 2985-2995 ◽  
Author(s):  
JoAnn M. Tufariello ◽  
Kaixia Mi ◽  
Jiayong Xu ◽  
Yukari C. Manabe ◽  
Anup K. Kesavan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mycobacterium Tuberculosis ◽  
Human Population ◽  
Acute Infection ◽  
Dependent Manner ◽  
Survival Times ◽  
Chronic Infections ◽  
Synthase Inhibitor

ABSTRACT Approximately one-third of the human population is latently infected with Mycobacterium tuberculosis, comprising a critical reservoir for disease reactivation. Despite the importance of latency in maintaining M. tuberculosis in the human population, little is known about the mycobacterial factors that regulate persistence and reactivation. Previous in vitro studies have implicated a family of five related M. tuberculosis proteins, called resuscitation promoting factors (Rpfs), in regulating mycobacterial growth. We studied the in vivo role of M. tuberculosis rpf genes in an established mouse model of M. tuberculosis persistence and reactivation. After an aerosol infection with the M. tuberculosis Erdman wild type (Erdman) or single-deletion rpf mutants to establish chronic infections in mice, reactivation was induced by administration of the nitric oxide (NO) synthase inhibitor aminoguanidine. Of the five rpf deletion mutants tested, one (ΔRv1009) exhibited a delayed reactivation phenotype, manifested by delayed postreactivation growth kinetics and prolonged median survival times among infected animals. Immunophenotypic analysis suggested differences in pulmonary B-cell responses between Erdman- and ΔRv1009-infected mice at advanced stages of reactivation. Analysis of rpf gene expression in the lungs of Erdman-infected mice revealed that relative expression of four of the five rpf-like genes was diminished at late times following reactivation, when bacterial numbers had increased substantially, suggesting that rpf gene expression may be regulated in a growth phase-dependent manner. To our knowledge, ΔRv1009 is the first M. tuberculosis mutant to have a specific defect in reactivation without accompanying growth defects in vitro or during acute infection in vivo.

scholarly journals A Neutralizing Prolactin Receptor Antibody Whose In Vivo Application Mimics the Phenotype of Female Prolactin Receptor-Deficient Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4365-4373 ◽  
Author(s):  
Christiane Otto ◽  
Anna Särnefält ◽  
Anne Ljungars ◽  
Siegmund Wolf ◽  
Beate Rohde-Schulz ◽  
...  
Keyword(s):  
Prolactin Receptor ◽  
Human Monoclonal Antibody ◽  
Negative Control ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Female Mice ◽  
Prolactin Synthesis ◽  
Deficient Mice

The prolactin receptor (PRLR) has been implicated in a variety of physiological processes (lactation, reproduction) and diseases (breast cancer, autoimmune diseases). Prolactin synthesis in the pituitary and extrapituitary sites is regulated by different promoters. Dopamine receptor agonists such as bromocriptine can only interfere with pituitary prolactin synthesis and thus do not induce a complete blockade of PRLR signaling. Here we describe the identification of a human monoclonal antibody 005-C04 that blocks PRLR-mediated signaling at nanomolar concentrations in vitro. In contrast to a negative control antibody, the neutralizing PRLR antibody 005-C04 inhibits signal transducer and activator of transcription 5 phosphorylation in T47D cells and proliferation of BaF3 cells stably expressing murine or human PRLRs in a dose-dependent manner. In vivo application of this new function-blocking PRLR antibody reflects the phenotype of PRLR-deficient mice. After antibody administration female mice become infertile in a reversible manner. In lactating dams, the antibody induces mammary gland involution and negatively interferes with lactation capacity as evidenced by reduced milk protein expression in mammary glands and impaired litter weight gain. Antibody-mediated blockade of the PRLR in vivo stimulates hair regrowth in female mice. Compared with peptide-derived PRLR antagonists, the PRLR antibody 005-C04 exhibits several advantages such as higher potency, noncompetitive inhibition of PRLR signaling, and a longer half-life, which allows its use as a tool compound also in long-term in vivo studies. Therefore, we suggest that this antibody will help to further our understanding of the role of auto- and paracrine PRLR signaling in health and disease.

scholarly journals β-Chemokines Enhance Parasite Uptake and Promote Nitric Oxide-Dependent Microbiostatic Activity in Murine Inflammatory Macrophages Infected with Trypanosoma cruzi

1999 ◽  
Vol 67 (9) ◽  
pp. 4819-4826 ◽  
Author(s):  
Júlio C. S. Aliberti ◽  
Fabiana S. Machado ◽  
Janeusa T. Souto ◽  
Ana P. Campanelli ◽  
Mauro M. Teixeira ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Neutralizing Antibodies ◽  
Specific Inhibitor ◽  
No Production ◽  
Dependent Manner ◽  
Macrophage Infection ◽  
Parasite Replication ◽  
Ifn Γ

ABSTRACT In the present study, we describe the ability of Trypanosoma cruzi trypomastigotes to stimulate the synthesis of β-chemokines by macrophages. In vivo infection with T. cruzi led to MIP-1α, RANTES, and JE/MCP1 mRNA expression by cells from peritoneal inflammatory exudate. In addition, in vitro infection with T. cruzi resulted in expression of β-chemokine MIP-1α, MIP-1β, RANTES, and JE mRNA by macrophages. The expression of the β-chemokine MIP-1α, MIP-1β, RANTES, and JE proteins by murine macrophages cultured with trypomastigote forms ofT. cruzi was confirmed by immunocytochemistry. Interestingly, macrophage infection with T. cruzi also resulted in NO production, which we found to be mediated mainly by β-chemokines. Hence, treatment with anti-β-chemokine-specific neutralizing antibodies partially inhibited NO release by macrophages incubated with T. cruzi parasites. Further, the addition of the exogenous β-chemokines MIP-1α, MIP-1β, RANTES, and JE/MCP-1 induced an increased T. cruzi uptake, leading to enhanced NO production and control of parasite replication in a dose-dependent manner. l-NMMA, a specific inhibitor of thel-arginine–NO pathway, caused a decrease in NO production and parasite killing when added to cultures of macrophages stimulated with β-chemokines. Among the β-chemokines tested, JE was more potent in inhibiting parasite growth, although it was much less efficient than gamma interferon (IFN-γ). Nevertheless, JE potentiates parasite killing by macrophages incubated with low doses of IFN-γ. Together, these results suggest that in addition to their chemotactic activity, murine β-chemokines may also contribute to enhancing parasite uptake and promoting control of parasite replication in macrophages and may play a role in resistance to T. cruziinfection.

scholarly journals A novel hamster model of SARS-CoV-2 respiratory infection using a pseudotyped virus

2021 ◽  
Author(s):  
Hiroshi Yamada ◽  
Soichiro Sasaki ◽  
Hideki Tani ◽  
Mayu Somekawa ◽  
Hitoshi Kawasuji ◽  
...  
Keyword(s):  
Imaging System ◽  
Respiratory Infections ◽  
Transgenic Animals ◽  
Future Research ◽  
Pseudotyped Virus ◽  
Dependent Manner ◽  
Hamster Model ◽  
Viral Binding

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a biosafety level (BSL)-3 pathogen; therefore, its research environment is strictly limited. Pseudotyped viruses that mimic SARS-CoV-2 have been widely used for in vitro evaluation because they are available in BSL-2 containment laboratories; however, in vivo application is inadequate. Therefore, animal models that can be instigated with animal BSL-2 will increase opportunities for in vivo evaluations. Methods: Hamsters (6- to 10-week-old males) were intratracheally inoculated with luciferase-expressing vesicular stomatitis virus (VSV)-based SARS-CoV-2 pseudotyped virus. The lungs were harvested 24 h after inoculation, and luminescence was measured using an in vivo imaging system. Results: Lung luminescence after inoculation with the SARS-CoV-2 pseudotyped virus increased in a dose-dependent manner. VSV-G (envelope [G]) pseudotyped virus also induced luminescence; however, a 100-fold concentration was required to reach a level similar to that of the SARS-CoV-2 pseudotyped virus. Conclusions: The SARS-CoV-2 pseudotyped virus is applicable to SARS-CoV-2 respiratory infections in a hamster model. Because of the single-round infectious virus, the model can be used to study the steps from viral binding to entry, which will be useful for future research regarding SARS-CoV-2 entry without using live SARS-CoV-2 or transgenic animals.

scholarly journals Adipocyte-specific modulation of KLF14 expression in mice leads to sex-dependent impacts in adiposity and lipid metabolism

2021 ◽  
Author(s):  
Qianyi Yang ◽  
Jameson Hinkle ◽  
Jordan N Reed ◽  
Redouane Aherrahrou ◽  
Zhiwen Xu ◽  
...  
Keyword(s):  
Fat Mass ◽  
Risk Allele ◽  
Lipid Storage ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Male Mice ◽  
Adipose Tissues ◽  
Female Mice ◽  
Fat Depots ◽  
Deficient Mice

Genome-wide association studies identified single nucleotide polymorphisms on chromosome 7 upstream of KLF14 to be associated with metabolic syndrome traits and increased risk for Type 2 Diabetes (T2D). The associations were more significant in women than in men. The risk allele carriers expressed lower levels of the transcription factor KLF14 in adipose tissues than non-risk allele carriers. To investigate how adipocyte KLF14 regulates metabolic traits in a sex-dependent manner, we characterized high-fat diet fed male and female mice with adipocyte-specific Klf14 deletion or overexpression. Klf14 deletion resulted in increased fat mass in female mice and decreased fat mass in male mice. Female Klf14-deficient mice had overall smaller adipocytes in subcutaneous fat depots but larger adipocytes in parametrial depots, indicating a shift in lipid storage from subcutaneous to visceral fat depots. They had reduced metabolic rates and increased respiratory exchange ratios consistent with increased utilization of carbohydrates as an energy source. Fasting and isoproterenol-induced adipocyte lipolysis was defective in female Klf14-deficient mice and concomitantly adipocyte triglycerides lipase mRNA levels were downregulated. Female Klf14-deficient mice cleared blood triglyceride and NEFA less efficiently than wild type. Finally, adipocyte-specific overexpression of Klf14 resulted in lower total body fat in female but not male mice. Taken together, consistent with human studies, adipocyte KLF14 deficiency in female but not in male mice causes increased adiposity and redistribution of lipid storage from subcutaneous to visceral adipose tissues. Increasing KLF14 abundance in adipocytes of females with obesity and T2D may provide a novel treatment option to alleviate metabolic abnormalities.

scholarly journals A Trypanosoma cruzi strain from southern Mexico is more virulent for male mice in part by blocking the immune response

2021 ◽  
Vol 15 (11) ◽  
pp. 1714-1723
Author(s):  
Celeste Amaranta Palma-González ◽  
Héctor Israel Recinos-Vázquez ◽  
Julio César Burguete-Gutiérrez ◽  
José Antonio De Fuentes-Vicente ◽  
María Adelina Schlie-Guzmán ◽  
...  
Keyword(s):  
Immune Response ◽  
Latin America ◽  
Chagas Disease ◽  
Scientific Basis ◽  
Male Mice ◽  
American Continent ◽  
Endemic Region ◽  
Southern Mexico ◽  
Female Mice ◽  
Mexican State

Introduction: Chagas disease is a neglected disease in the American continent. The southern Mexican state of Chiapas has the highest incidence rate of Chagas disease in the country. The disease, mainly caused by Tripanosoma cruzi in Mexico, is more prevalent in males than in females but the scientific basis for the sex-related tropism is not completely understood. The objective of this study was to evaluate the pathogenicity of a T. cruzi strain in mice of both sexes and to assess certain elements of the immune response in the infected animals. Methodology: Triatomines bugs were searched at Los Mezcales, Chiapas, Mexico and T. cruzi was identified by PCR and sequencing. A T. cruzi strain was isolated from the feces of triatomines bugs. Mice were infected with the strain and the virulence of the T. cruzi strain as well as the immune response against the infection was compared in male versus female mice. Results: T. dimidiata was identified in all dwellings. 42.9% of the bugs were infected with T. cruzi lineage TcI. Male mice exhibited higher parasitemia than females, and developed leukopenia and lower levels of anti-T. cruzi antibodies compared to female mice. Conclusions: The identification of the T. cruzi strain in this endemic region of Mexico revealed that male mice are prone to this infectious protozoo, in addition to manifesting a deficient immune response against infection. These findings may explain the greater number of cases of Chagas disease among men in this endemic region of Latin America.

scholarly journals The Blockade of Interleukin-2 During the Acute Phase of Trypanosoma cruzi Infection Reveals Its Dominant Regulatory Role

2021 ◽  
Vol 11 ◽  
Author(s):  
Jorge Nihei ◽  
Fabiola Cardillo ◽  
Jose Mengel
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Regulatory T Cells ◽  
Trypanosoma Cruzi ◽  
Immune Responses ◽  
Chagas Disease ◽  
Acute Phase ◽  
Acute Infection ◽  
Dependent Manner ◽  
Tissue Specific

Trypanosoma cruzi infection causes Chagas’ disease in humans. The infection activates the innate and adaptative immunity in an orchestrated immune response to control parasite growth, guaranteeing host survival. Despite an effective immune response to the parasite in the acute phase, the infection progresses to a chronic stage. The parasite infects different tissues such as peripheral neurons, the brain, skeletal muscle, and heart muscle, among many others. It is evident now that tissue-specific immune responses may develop along with anti-parasite immunity. Therefore, mechanisms to regulate immunity and to ensure tissue-specific tolerance are operating during the infection. Studying those immunoregulatory mechanisms is fundamental to improve host protection or control inflammatory reactions that may lead to pathology. The role of IL-2 during T. cruzi infection is not established. IL-2 production by T cells is strongly down-modulated early in the disease by unknown mechanisms and remains low during the chronic phase of the disease. IL-2 activates NK cells, CD4, and CD8 T cells and may be necessary to immunity development. Also, the expansion and maintenance of regulatory T cells require IL-2. Thus, IL-2 may be a key cytokine involved in promoting or down-regulating immune responses, probably in a dose-dependent manner. This study blocked IL-2 during the acute T. cruzi infection by using a neutralizing monoclonal antibody. The results show that parasitemia and mortality rate was lower in animals treated with anti-IL-2. The percentages and total numbers of CD4+CD25+Foxp3+ T cells diminished within three weeks of infection. The numbers of splenic activated/memory CD4 and CD8 splenic T cells increased during the acute infection. T cells producing IFN-γ, TNF-α and IL-10 also augmented in anti-IL-2-treated infected mice. The IL-2 blockade also increased the numbers of inflammatory cells in the heart and skeletal muscles and the amount of IL-17 produced by heart T cells. These results suggest that IL-2 might be involved in the immune regulatory response during the acute T. cruzi infection, dampening T cell activation through the expansion/maintenance of regulatory T cells and regulating IL-17 production. Therefore, the IL-2 pathway is an attractive target for therapeutic purposes in acute and chronic phases of Chagas’ disease.

scholarly journals Complement Is an Essential Component of the Immune Response to Adeno-Associated Virus Vectors

2008 ◽  
Vol 82 (6) ◽  
pp. 2727-2740 ◽  
Author(s):  
Anne K. Zaiss ◽  
Matthew J. Cotter ◽  
Lindsay R. White ◽  
Sharon A. Clark ◽  
Norman C. W. Wong ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Human Serum ◽  
Factor H ◽  
Dependent Manner ◽  
Adeno Associated Virus ◽  
Essential Component ◽  
Primary Mouse ◽  
Mouse Macrophages

ABSTRACT Adeno-associated virus (AAV) vectors are associated with relatively mild host immune responses in vivo. Although AAV induces very weak innate immune responses, neutralizing antibodies against the vector capsid and transgene still occur. To understand further the basis of the antiviral immune response to AAV vectors, studies were performed to characterize AAV interactions with macrophages. Primary mouse macrophages and human THP-1 cells transduced in vitro using an AAV serotype 2 (AAV2) vector encoding green fluorescent protein did not result in measurable transgene expression. An assessment of internalized vector genomes showed that AAV2 vector uptake was enhanced in the presence of normal but not heat-inactivated or C3-depleted mouse/human serum. Enhanced uptake in the presence of serum coincided with increased macrophage activation as determined by the expression of NF-κB-dependent genes such as macrophage inflammatory protein 2 (MIP-2), interleukin-1β (IL-1β), IL-8, and MIP-1β. AAV vector serotypes 1 and 8 also activated human and mouse macrophages in a serum-dependent manner. Immunoprecipitation studies demonstrated the binding of iC3b complement protein to the AAV2 capsid in human serum. AAV2 did not activate the alternative pathway of the complement cascade and lacked cofactor activity for factor I-mediated degradation of C3b to iC3b. Instead, our results suggest that the AAV capsid also binds complement regulatory protein factor H. In vivo, complement receptor 1/2- and C3-deficient mice displayed impaired humoral immunity against AAV2 vectors, with a delay in antibody development and significantly lower neutralizing antibody titers. These results show that the complement system is an essential component of the host immune response to AAV.

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