Biology subjects

Longhini, A. L. F.

Publications and source records attributed to Longhini, A. L. F..

3 recordsLinked to original sources

bioRxiv2024

Chlamydia muridarum Causes Persistent Subclinical Infection and Elicits Innate and Adaptive Immune Responses in C57BL/6J, BALB/cJ and J:ARC(S) Mice Following Exposure to Shedding Mice

Chlamydia muridarum (Cm) has reemerged as a moderately prevalent infectious agent in research mouse colonies. Despite its experimental use, few studies evaluate Cms effects on immunocompetent mice following its natural route of infection. A Cm field isolate was administered (orogastric gavage) to 8-week-old female BALB/cJ (C) mice. After confirming shedding (through 95d), these mice were cohoused with naive C57BL/6J (B6), C, and Swiss (J:ARC[S]) mice (n=28/strain) for 30 days. Cohoused mice (n=3-6 exposed and 1-6 control/strain) were evaluated 7, 14, 21, 63, 120, and 180 days post-cohousing (DPC) via hemograms, serum biochemistry analysis, fecal qPCR, histopathology, and Cm MOMP immunohistochemistry. Immunophenotyping was performed on spleen (B6, C, S; n=6/strain) and intestines (B6; n=6) at 14 and 63 DPC. Serum cytokine concentrations were measured (B6; n=6 exposed and 2 control) at 14 and 63 DPC. All B6 mice were shedding Cm by 3 through 180 DPI. One of 3 C and 1 of 6 S mice began shedding Cm at 3 and 14 DPC, respectively, with the remaining shedding thereafter. Clinical pathology was nonremarkable. Minimal-to-moderate enterotyphlocolitis and gastrointestinal associated lymphoid tissue (GALT) hyperplasia was observed in 15 and 47 of 76 Cm-infected mice, respectively. Cm antigen was frequently detected in GALT-associated surface intestinal epithelial cells. Splenic immunophenotyping revealed increased monocytes and shifts in T cell population subsets in all strains/timepoints. Gastrointestinal immunophenotyping (B6) revealed sustained increases in total inflammatory cells and elevated cytokine production in innate lymphoid cells and effector T cells (large intestine). Elevated concentrations of pro-inflammatory cytokines were detected in the serum (B6). Results demonstrate that while clinical disease was not appreciated, 3 commonly utilized strains of mice are susceptible to chronic enteric Cm infection which may alter various immune responses. Considering the widespread use of mice to model GI disease, institutions should consider excluding Cm from their colonies.

microbiology↗

bioRxiv2023

Interferon response and epigenetic modulation by SMARCA4 mutations drive ovarian tumor immunogenicity

Cell-intrinsic mechanisms of immunogenicity in ovarian cancer (OC) are not well understood. The presence of damaging mutations in the SWI/SNF chromatin remodeling complex, such as the SMARCA4 (BRG1) catalytic subunit, has been associated with improved response to ICB, however the mechanism by which this occurs is unclear. The aim of this current study was to examine the alterations in tumor cell-intrinsic and extrinsic immune signaling caused by SMARCA4 loss. Using OC models with loss-of-function mutations in SMARCA4, we found that SMARCA4 loss resulted in increased cancer cell-intrinsic immunogenicity, characterized by upregulation of long-terminal RNA repeats such as endogenous retroviruses, increased expression of interferon-stimulated genes, and upregulation of antigen presentation machinery. Notably, this response was dependent on IRF3 signaling, but was independent of the type I interferon receptor. Mice inoculated with cancer cells bearing SMARCA4 loss demonstrated increased activation of cytotoxic T cells and NK cells in the tumor microenvironment as well as increased infiltration with activated dendritic cells. These results were recapitulated when animals bearing SMARCA4-proficient tumors were treated with a BRG1 inhibitor, suggesting that modulation of chromatin remodeling through targeting SMARCA4 may serve as a strategy to reverse immune evasion in OC.

cancer biology↗

bioRxiv2021

Depleting Hypothalamic Somatostatinergic Neurons Recapitulates Diabetic Phenotypes in Brain, Bone Marrow, Adipose, and Retina

Hypothalamic inflammation and sympathetic nervous system hyperactivity are hallmark features of metabolic syndrome and type 2 diabetes. Hypothalamic inflammation may aggravate metabolic and immunologic pathologies due to extensive sympathetic activation of peripheral tissues. Loss of somatostatinergic (SST) neurons may contribute to enhanced hypothalamic inflammation. The present data show that leptin receptor deficient (db/db) mice exhibit reduced hypothalamic somatostatinergic cells, particularly in the periventricular nucleus. We model this finding, using adeno-associated virus (AAV) delivery of diphtheria toxin (DTA) driven by an SST-cre system to deplete these cells in SSTcre/gfp mice (SST-DTA). SST-DTA mice exhibit enhanced hypothalamic c-fos expression and brain inflammation as demonstrated by microglial and astrocytic activation. Bone marrow from SST-DTA mice undergoes skewed hematopoiesis, generating excess granulocyte-monocyte precursors and increased pro-inflammatory (CCR2hi) monocytes. Visceral adipose tissue from DTA-treated animals was resistant to catecholamine induced lipolysis. Finally, SST-DTA mice exhibited a "diabetic retinopathy like" phenotype: reduced visual function by optokinetic response and electroretinogram, as well as increased percentages of retinal monocytes. Importantly, hyperglycemia was not observed in SST-DTA mice. Thus, the isolated reduction in hypothalamic somatostatinergic neurons was able to recapitulate several hallmark features of type 2 diabetes in disease relevant tissues.

neuroscience↗