LB010/#1590  A phase 2 randomized dose optimization trial of gotistobart, a PH-sensitive anti-CTLA-4, in combination with pembrolizumab in platinum-resistant ovarian cancer (PROC, preserve-004/GOG-3081; NCT05446298)

International Journal of Gynecological Cancer · 2024-10-01

An intranasal recombinant NDV-BRSV Fopt vaccine is safe and reduces lesion severity in a colostrum-deprived calf model of RSV infection

Scientific Reports · 2022-12-29 · 2 citations

Abstract Human respiratory syncytial virus (HRSV) is a major cause of severe lower respiratory tract disease in infants and the elderly, yet no safe, effective vaccine is commercially available. Closely related bovine RSV (BRSV) causes respiratory disease in young calves, with many similar features to those seen in HRSV. We previously showed that a Newcastle disease virus (NDV)-vectored vaccine expressing the F glycoprotein of HRSV reduced viral loads in lungs of mice and cotton rats and protected from HRSV. However, clinical signs and pathogenesis of disease in laboratory animals following HRSV infection differs from that observed in human infants. Thus, we examined whether a similar vaccine would protect neonatal calves from BRSV infection. Codon-optimized rNDV vaccine (rNDV-BRSV F opt ) was constructed and administered to colostrum-deprived calves. The rNDV-BRSV F opt vaccine was well-tolerated and there was no evidence of vaccine-enhanced disease in the upper airways or lungs of these calves compared to the non-vaccinated calves. We found two intranasal doses reduces severity of gross and microscopic lesions and decreases viral load in the lungs. Furthermore, serum neutralizing antibodies were generated in vaccinated calves. Finally, reduced lung CXC chemokine levels were observed in vaccinated calves after BRSV challenge. In summary, we have shown that rNDV-BRSV F opt vaccine is safe in colostrum-deprived calves, and is effective in reducing lung lesions, and decreasing viral load in upper respiratory tract and lungs after challenge.

Critical role of interferons in gastrointestinal injury repair

Nature Communications · 2021 · 86 citations

• Immunology
• Biology
• Cancer research

Abstract The etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators. Here we use IFN receptor-deficient mice in a dextran sulfate sodium (DSS) model of acute intestinal injury to study the contributions of type I and III interferons (IFN) to the initiation, progression and resolution of acute colitis. We find that mice lacking both types of IFN receptors exhibit enhanced barrier destruction, extensive loss of goblet cells and diminished proliferation of epithelial cells in the colon following DSS-induced damage. Impaired mucosal healing in double IFN receptor-deficient mice is driven by decreased amphiregulin expression, which IFN signaling can up-regulate in either the epithelial or hematopoietic compartment. Together, these data underscore the pleiotropic functions of IFNs and demonstrate that these critical antiviral cytokines also support epithelial regeneration following acute colonic injury.

The <i>In Vivo</i> Source of Type I and Type III IFNs is Pathogen Dependent

bioRxiv (Cold Spring Harbor Laboratory) · 2021-10-05 · 6 citations

Abstract Type I (-α, β) and type III (-λ) interferons (IFNs) are produced in response to virus infection and upregulate a largely overlapping set of IFN stimulated genes which mediate the protective effects of these antiviral cytokines. In vitro studies have demonstrated the redundancy of these two cytokine families which activate the same transcription factor, IFN stimulated gene factor 3 (ISGF3), via distinct ligands and receptors. However, in vivo , these IFN types do have distinct functions based on receptor distribution, but also ligand availability. Using a newly generated IFN-λ reporter mouse strain we have observed that both type I and type III IFNs are produced in response to respiratory tract infection by Newcastle disease virus (NDV) and influenza A virus (IAV). In the case of NDV these IFNs are synthesized by different cell types. Type I IFNs are produced primarily by alveolar macrophages, type III IFNs are made only by epithelial cells, and production of either is dependent on MAVS. While epithelial cells of the respiratory tract represent the primary target of IAV infection, we found that they did not significantly contribute to IFN-λ production, and IFN-λ protein levels were largely unaffected in the absence of MAVS. Instead we found that pDCs, a cell type known for robust IFN-α production via TLR/MyD88 signaling, were the major producers of IFN-λ during IAV infection, with pDC depletion during influenza infection resulting in significantly reduced levels of both IFN-α and IFN-λ. In addition, we were able to demonstrate that pDCs rely on type I IFN for optimal IFN-λ production. These studies therefore demonstrate that the in vivo producers of Type III IFNs in response to respiratory virus infection are pathogen dependent, a finding which may explain the varying levels of cytokine production induced by different viral pathogens.

COVID-19 and emerging viral infections: The case for interferon lambda

The Journal of Experimental Medicine · 2020 · 207 citations

• Virology
• Medicine
• Immunology

With the first reports on coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the scientific community working in the field of type III IFNs (IFN-λ) realized that this class of IFNs could play an important role in this and other emerging viral infections. In this Viewpoint, we present our opinion on the benefits and potential limitations of using IFN-λ to prevent, limit, and treat these dangerous viral infections.

Distinct contributions of Type I and Type III IFNs in innate fungal immunity

The Journal of Immunology · 2020-05-01

Abstract Type I (IFN-α/β) and Type III (IFN-λ) interferons are important mediators of antiviral immunity but whether they are required for antifungal defense is unclear. We report that mice defective in Type I and/or Type III IFN receptor expression are highly susceptible to infection with the opportunistic human fungal pathogen Aspergillus fumigatus (Af). Type I IFN (IFNAR) and Type III (IFNLR1) receptor expression on hematopoietic cells was required for antifungal defense while their expression on non-hematopoietic was dispensable. Consistently, mice with gene-specific deletion of IFNLR1 or STAT-1 on granulocytes were highly susceptible to Af. These data demonstrate a requisite and non-redundant role for Type I and Type III IFNs for the activation of antifungal immunity. In addition, we found that Type III IFNs act as important activators of reactive oxygen species generation in antifungal neutrophils, and require early expression of Type I IFN for optimal induction. Importantly, CCR2+ monocytes act as an important source of Type I IFN, and are required for the optimal expression of Type III IFN and fully functional neutrophil antifungal activity. Dysfunctional neutrophil responses in CCR2-depleted mice were rescued by adoptive transfer of pulmonary CCR2+ monocytes or by exogenous administration of IFN-a and IFN-l. Altogether, our data identified Type III IFNs as major regulators of neutrophil activation, and Type I IFNs as early activators of IFN-λ expression and response. Innate antifungal defense is thus coordinated by the actions of Type I and Type III IFNs, a finding that suggests a broader therapeutic potential for these cytokines as activators of antifungal immunity.

Influenza A Virus Inhibits Alveolar Fluid Clearance in BALB/c Mice

UNC Libraries · 2020-10-30

Rationale: Pulmonary infections can impair alveolar fluid clearance (AFC), contributing to formation of lung edema. Effects of influenza A virus (IAV) on AFC are unknown.

Calcium Activation of Mitochondrial Respiration is Maintained in Heart Failure Despite Altered Mitochondrial Membrane Potential

TopSCHOLAR (Western Kentucky University) · 2020-01-01

Click the PDF icon to download the abstract.

Type III IFNs: Beyond antiviral protection

Seminars in Immunology · 2019-06-01 · 140 citations

Transmission phenotype of Mycobacterium tuberculosis strains is mechanistically linked to induction of distinct pulmonary pathology

PLoS Pathogens · 2019-03-06 · 49 citations

In a study of household contacts (HHC), households were categorized into High (HT) and Low (LT) transmission groups based on the proportion of HHC with a positive tuberculin skin test. The Mycobacterium tuberculosis (Mtb) strains from HT and LT index cases of the households were designated Mtb-HT and Mtb-LT, respectively. We found that C3HeB/FeJ mice infected with Mtb-LT strains exhibited significantly higher bacterial burden compared to Mtb-HT strains and also developed diffused inflammatory lung pathology. In stark contrast, a significant number of mice infected with Mtb-HT strains developed caseating granulomas, a lesion type with high potential to cavitate. None of the Mtb-HT infected animals developed diffused inflammatory lung pathology. A link was observed between increased in vitro replication of Mtb-LT strains and their ability to induce significantly high lipid droplet formation in macrophages. These results support that distinct early interactions of Mtb-HT and Mtb-LT strains with macrophages and subsequent differential trajectories in pathological disease may be the mechanism underlying their transmission potential.