Role of interferon‐γ and inflammatory monocytes in driving colonic inflammation during acute Clostridium difficile infection in mice

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136491/1/imm12700.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136491/2/imm12700_am.pd

The role of Gr‐1+ cells and tumour necrosis factor‐α signalling during Clostridium difficile colitis in mice

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110845/1/imm12425.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/110845/2/imm12425-sup-0001-FigS1-2.pd

Interleukin‐22 and CD160 play additive roles in the host mucosal response to Clostridium difficile infection in mice

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110834/1/imm12414.pd

Comparative genomics explains the evolutionary success of reef-forming corals

Transcriptome and genome data from twenty stony coral species and a selection of reference bilaterians were studied to elucidate coral evolutionary history. We identified genes that encode the proteins responsible for the precipitation and aggregation of the aragonite skeleton on which the organisms live, and revealed a network of environmental sensors that coordinate responses of the host animals to temperature, light, and pH. Furthermore, we describe a variety of stress-related pathways, including apoptotic pathways that allow the host animals to detoxify reactive oxygen and nitrogen species that are generated by their intracellular photosynthetic symbionts, and determine the fate of corals under environmental stress. Some of these genes arose through horizontal gene transfer and comprise at least 0.2% of the animal gene inventory. Our analysis elucidates the evolutionary strategies that have allowed symbiotic corals to adapt and thrive for hundreds of millions of years.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by eLife Sciences Publications. The published article can be found at: https://elifesciences.org

Role of Neutrophils in Preventing and Resolving Acute Fungal Sinusitis▿ †

Acute fungal sinusitis (AFS) is a devastating disease of the paranasal sinuses afflicting immunocompromised individuals. Knowledge about this disease is limited to clinical observations because there are no animal models in which to study the pathogenesis of the infection. Our goal was to develop a murine model of AFS and examine the role of neutrophils in host defense within the nasal cavity. Female C57BL/6 mice were depleted of neutrophils using anti-Gr-1 monoclonal antibody from day −1 to day 5 postinfection to initiate a transient neutropenia within the mice. At day 0, Aspergillus fumigatus conidia were administered intranasally. The untreated Aspergillus-exposed group had significant neutrophil recruitment by day 3, but by day 7 the leukocyte numbers had returned to unexposed levels. There was not a significant influx of mononuclear cells at either time point. In contrast, beginning at day 3 postinfection and continuing through day 7, anti-Gr-1-treated mice had increased cellular recruitment consisting of banded neutrophils at day 3 and mature neutrophils at day 7. Hyphal masses developed only in the anti-Gr-1-treated mice (25 to 36%) but only during the period of treatment. When the treatment was discontinued, hyphal masses could no longer be detected in the nasal cavities of these mice. In contrast, cyclophosphamide treatment did not induce neutropenia, and the nasal cavity remained free of hyphal masses. These studies demonstrate the feasibility of using this model to study AFS and implicate neutrophils in protection of the sinuses against acute Aspergillus infection and in clearance of established hyphal masses

Transient Neutralization of Tumor Necrosis Factor Alpha Can Produce a Chronic Fungal Infection in an Immunocompetent Host: Potential Role of Immature Dendritic Cells

The mechanisms underlying induction of immune dysregulation and chronic fungal infection by a transient tumor necrosis factor alpha (TNF-α) deficiency remain to be defined. The objective of our studies was to determine the potential contribution of neutropenia and immature dendritic cells to the immune deviation. Administration of an anti-TNF-α monoclonal antibody at day 0 neutralized TNF-α only during the first week of a pulmonary Cryptococcus neoformans infection. Transient neutralization of TNF-α resulted in transient depression of interleukin-12 (IL-12), monocyte chemotactic protein 1 (MCP-1), and gamma interferon (IFN-γ) production but permanently impaired long-term clearance of the infection from the lungs even after the levels of these cytokines increased and a vigorous inflammatory response developed. Early neutrophil recruitment was defective in the absence of TNF-α. However, as demonstrated by neutrophil depletion studies, this did not account for the decrease in IL-12 and IFN-γ levels and did not play a role in establishing chronic pulmonary cryptococcal infection. Transient TNF-α neutralization also produced a deficiency in CD11c(+) MHC II(+) cells and IL-12 in the lymph nodes, potentially implicating a defect in mature dendritic cell trafficking. Transfer of cryptococcal antigen-pulsed immature dendritic cells into naïve mice prior to intratracheal challenge resulted in the development of a nonprotective immune response to C. neoformans that was similar to that observed in anti-TNF-α-treated mice (increased IL-4, IL-5, and IL-10 levels, pulmonary eosinophilia, and decreased clearance). Thus, stimulation of an antifungal response by immature dendritic cells can result in an immune deviation similar to that produced by transient TNF-α deficiency, identifying a new mechanism by which a chronic fungal infection can occur in an immunocompetent host

Correction to: Whole lung tissue is the preferred sampling method for amplicon-based characterization of murine lung microbiota

http://deepblue.lib.umich.edu/bitstream/2027.42/173982/1/40168_2021_Article_1121.pd

Whole lung tissue is the preferred sampling method for amplicon-based characterization of murine lung microbiota

Abstract Background Low-biomass microbiome studies (such as those of the lungs, placenta, and skin) are vulnerable to contamination and sequencing stochasticity, which obscure legitimate microbial signal. While human lung microbiome studies have rigorously identified sampling strategies that reliably capture microbial signal from these low-biomass microbial communities, the optimal sampling strategy for characterizing murine lung microbiota has not been empirically determined. Performing accurate, reliable characterization of murine lung microbiota and distinguishing true microbial signal from noise in these samples will be critical for further mechanistic microbiome studies in mice. Results Using an analytic approach grounded in microbial ecology, we compared bacterial DNA from the lungs of healthy adult mice collected via two common sampling approaches: homogenized whole lung tissue and bronchoalveolar lavage (BAL) fluid. We quantified bacterial DNA using droplet digital PCR, characterized bacterial communities using 16S rRNA gene sequencing, and systematically assessed the quantity and identity of bacterial DNA in both specimen types. We compared bacteria detected in lung specimens to each other and to potential source communities: negative (background) control specimens and paired oral samples. By all measures, whole lung tissue in mice contained greater bacterial signal and less evidence of contamination than did BAL fluid. Relative to BAL fluid, whole lung tissue exhibited a greater quantity of bacterial DNA, distinct community composition, decreased sample-to-sample variation, and greater biological plausibility when compared to potential source communities. In contrast, bacteria detected in BAL fluid were minimally different from those of procedural, reagent, and sequencing controls. Conclusions An ecology-based analytical approach discriminates signal from noise in this low-biomass microbiome study and identifies whole lung tissue as the preferred specimen type for murine lung microbiome studies. Sequencing, analysis, and reporting of potential source communities, including negative control specimens and contiguous biological sites, are crucial for biological interpretation of low-biomass microbiome studies, independent of specimen type. Video abstracthttp://deepblue.lib.umich.edu/bitstream/2027.42/173981/1/40168_2021_Article_1055.pd