Guest ICIS Symposium at virtual AAI meeting IMMUNOLOGY2021, May 13, 2021
Emerging Roles of Type III Interferons in COVID-19, Gut Microbiome, Adaptive Immunity, and Anti-Fungal Immunity
The symposium started with a brief overview of type III IFNs by Sergei Kotenko, Rutgers University. He covered discoveries leading to the identification of this cytokine family and their receptor complex, introduced individual members of the IFN-lambda family, described the basic biology of type III IFNs, and reviewed their known functions. He presented differences between type I and type III IFN-based antiviral systems, emphasizing that type III IFNs are now well recognized for their important and indispensable role in protecting epithelial barriers against diverse viral pathogens. He also accentuated that since their discovery in 2003 and 2013, novel functions of IFN lambdas continue to be discovered, affecting diverse aspects of host immunity and homeostasis in health and disease, including various infections, cancer and autoimmune conditions. He briefly introduced the speakers and their presentation topics covering the role of type III IFNs in the gastrointestinal virus interaction with intestinal microbiota, antifungal immunity, adaptive immunity, tissue inflammation and integrity, and in COVID-19. Following the presentations, all speakers had an engaging Q&A session and answered questions and comments submitted through the chat.
The symposium included the following presentations.
Kristin Hogquist, University of Minnesota, “Distinct roles for type I and III interferons in thymic selection”.
We understand how the thymus achieves tolerance to tissue-restricted antigens through the action of a critical transcription regulator, AIRE. But how it achieves tolerance to temporal antigens, particularly those displayed during infections, is not understood. Here we showed that the thymus produces both type I and III IFNs at a steady state. These cytokines are produced primarily by medullary epithelial cells, particularly the MHC-ClassII/CD80 expressing “mTEChi” cells, and their expression in mTEChi cells is AIRE dependent. Using Mx1GFP reporter mice, RNAseq, and single-cell RNAseq in mice lacking Ifnar1, Ifnlr, both, or Stat1, we showed that multiple thymic APC types respond to type I and III IFNs, causing changes in antigen processing and presentation in addition to the expressed transcriptome. Thymocytes were sensitive only to type I IFN. B cells, in contrast, depended exclusively on type III IFNs for their activation and class switch properties. Using deep sequencing of expressed TCRS in WT and Ifnar1-/- mice, we showed that IFN profoundly impacts the T cell repertoire, changing approximately 2% of the conventional CD4 T cell repertoire and 10% of the Treg cell repertoire.
Megan Baldridge, Washington University Medical School, “Restriction of intestinal viral cellular tropism by IFN-lambda”.
IFN-lambda (IFN-λ) has been shown to mediate powerful antiviral effects in the intestine, playing important roles in controlling multiple enteric RNA viruses which infect intestinal epithelial cells. Persistent murine norovirus (MNoV) is sensitive to exogenous IFN-λ treatment, which acts via the IFN-λ receptor expressed on epithelial cells. Genetic disruption of either the receptor or IFN-λ cytokines permits enhanced viral replication of MNoV, and we have found that IFN-λ substantially restricts the cellular tropism of MNoV within the epithelium, with a 10-fold increase in infected permissive cells when IFN-λ signaling is disrupted, though the specific cell type infected (tuft cells) is unchanged. Importantly, MNoV has evolved mechanisms to evade IFN-λ signaling, specifically via secretion of a non-structural viral protein, which permits it to establish persistent infection in the epithelium. Despite differences in cellular tropism, we have observed similar effects of IFN-λ in regulating chronic murine astrovirus (muAstV) infection. Chronic muAstV infection in immunocompromised mice dramatically upregulates IFN-λ signaling, which in turn is important for limiting both infection by other viruses as well as controlling levels of muAstV itself. Again, while single-cell RNAseq has recently revealed that the general cell type(s) infected remain unchanged (goblet cells and enterocytes) when IFN-λ signaling is disrupted, a dramatic increase in the number of muAstV-infected cells is observed. Thus, in lieu of controlling the amount of virus produced within individual infected cells, IFN-λ serves to limit the number of infected cells in the intestinal epithelium to control multiple chronic enteric viral infections.
Amariliz Rivera, Rutgers-New Jersey Medical School, “Novel insights on IFN-lambda and the activation of innate antifungal immunity”.
Our studies have uncovered a novel role for type III IFN as the regulator of the antifungal response of neutrophils. We found that type I and III IFNs are both produced in response to pulmonary infection with the clinically important fungal pathogen Aspergillus fumigatus (Af). Production of type I IFN is very rapid and transient, while type III IFN is produced with delayed but sustained kinetics. IFN-l is best appreciated as a potent antiviral cytokine and several innate receptors are known to be involved in recognition of viral-derived nucleic acids to trigger its production. In the current study, we set out to examine pathways that may be involved in the production of type I and III IFNs in response to infection with Af. We determined that dectin-1-mediated recognition of Af-derived b-glucans is involved in the activation of type I and III IFNs. Dectin-1-/- mice had diminished production of both IFNs and succumbed to infection with Af-CEA10. Importantly, administration of recombinant type I and III IFNs to dectin-1-/- animals was able to significantly improve antifungal neutrophil responses and global control of infection (1). These findings suggest that dectin-1 promotes effective antifungal immunity at least in part by inducing optimal production of type I and III IFNs. In collaborative studies with Josh Obar’s laboratory, we further determined that the MDA5/MAVS pathway is also involved in the optimal production of IFN-l in response to infection with Af. Altogether, our studies suggest that IFN production in response to fungal infection is coordinated by early detection of b-glucan by dectin-1 followed by nucleic acid sensing by the MDA5/MAVS pathway. Some of the exciting questions for further study include the mechanism by which fungal RNA becomes accessible to the cytosol as well as what are the relevant cellular sources of IFN-l during infection with Af.
Ivan Zanoni, Harvard Medical School, Boston Children’s Hospital, “Impact and regulation of type III interferon production in COVID-19”.
The SARS-CoV-2 pandemic raised an unprecedented flux of studies aimed at unraveling the molecular mechanisms that determine severe COVID-19 and at identifying new therapies. Among available therapeutic options, the use of clinical-grade type I (IFN-I) or type III (IFN-III) families raised great hope and interest. IFN-III is particularly relevant, as it is notable for inducing an antiviral state while simultaneously limiting inflammation-driven tissue damage. Recombinant IFNs have been used in several COVID-19 clinical trials, leading, though, to somewhat inconclusive results. Our group recently demonstrated that, in a mouse model that mimics a viral infection, prolonged IFN-III production causes tissue damage and decreases the effectiveness of the lung barrier.
But are IFNs produced in COVID-19 patients? And are they good or bad? We recently collected new data from over 150 COVID-19 patients stratified by age and viral load. By analyzing gene and protein expression in the lower or upper airways, we revealed a complex picture that suggests IFN-III play opposing roles at distinct anatomical sites. Our data give a potent mandate to take into account the timing and localization of IFN-III production to explain their effectiveness in protecting against SARS-CoV-2.
Ludmila Prokunina-Olsson, National Cancer Institute, “Human genetics analysis identifies type III interferon-related biological mechanisms and treatments for COVID-19 and beyond”.
Variable response to SARS-CoV-2 infection suggests that host genetic factors might mediate this response and clinical severity of COVID-19 ranging from mild to fatal disease. Efforts of the COVID-19 Host Genetics Initiative (HGI), which compared infected individuals with the general population, reported 13 genome-wide significant loci harboring genes that might contribute to this differential immune response. Several of these loci include genes potentially involved in interferon signaling. We are performing a detailed genetic analysis of one of these genetic loci, which includes known antiviral genes OAS1 and OAS3 encoded on chromosome 12. In contrast to HGI efforts, our study is limited to patients. Specifically, our initial analysis is based on 1555 patients of European ancestry, including 566 patients with mild and 954 patients with hospitalized COVID- 19. We also analyzed the results of a clinical trial for outpatient COVID-19 in relation to genetic variants within the OAS1/OAS3 region. We demonstrated that both COVID-19 severity and the rate of clearance of SARS-COV-2 are dependent on the haplotypes of several OAS1 genetic variants that define the level of expression of OAS1 mRNA and its protection from nonsense-mediated decay (NMD). The rate of viral clearance after treatment with pegIFNλ1 was not associated with OAS1 genetic variants suggesting that early IFN treatment overcomes genetic deficiencies underlying impaired viral clearance. We also explored the association between genetic variants within the IFNL3/IFNL4 region with the same outcomes but did not observe any association. This analysis is now being expanded to include more patients.