Povroznik JM, Akhter H, Vance JK, Annamanedi M, Dziadowicz S, Wang, L, Divens A, Hu G, Robinson CM. Interleukin-27-dependent regulation of the transcriptome during neonatal sepsis. Front. Immunol. 2023; 14:1124140. doi: 10.3389/fimmu.2023.1124140.
Bradford SD, Witt MR, Povroznik JM, Robinson CM. Interleukin-27 impairs BCG antigen clearance and T cell stimulatory potential by neonatal dendritic cells. Curr Res Microb Sci. 2022; 4:100176. doi: 10.1016/j.crmicr.2022.100176.
Miller NW, Seman BG, Akers SM, Povroznik JM, Brundage K, Fang W, Robinson CM. The impact of opioid exposure during pregnancy on the human neonatal immune profile. Pediatr Res. 2022 Mar 14;1-9. doi: 10.1038/s41390-022-02014-x. Online ahead of print.
Seman BG, Robinson CM. The Enigma of Low-Density Granulocytes in Humans: Complexities in the Characterization and Function of LDGs during Disease. Pathogens. 2021; 10(9):1091.
Vance JK, Rawson TW, Povroznik JM, Brundage KM, Robinson CM. Myeloid-Derived Suppressor Cells Gain Suppressive Function during Neonatal Bacterial Sepsis. Int J Mol Sci. 2021; 22:7047.
Seman BG, Vance JK, Akers SM, Robinson CM. Neonatal low-density granulocytes internalize and kill bacteria but suppress monocyte function using extracellular DNA. J Cell Science. 2021; 134(5):jcs252528.
Seman BG, Povroznik JM, Vance JK, Rawson TW, Robinson CM. A Neonatal Imaging Model of Gram-Negative Bacterial Sepsis. J Vis. Exp. 2020; 162:e61609.
Seman BG, Vance JK, Rawson TW, Witt MR, Huckaby AB, Povroznik JM, Bradford SD, Barbier M, Robinson CM. Elevated levels of interleukin-27 in early life compromise protective immunity during neonatal sepsis. Infect Immun. 2019; 88(3):e00828-19.
Gleave Parson M, Grimmett J, Vance JK, Witt MR, Seman BG, Rawson TW, Lyda L, Labuda C, Jung JY, Bradford SD, Robinson CM. Murine myeloid-derived suppressor cells are a source of elevated levels of interleukin-27 in early life and compromise control of bacterial infection. Immunol Cell Biol. 2019; 97:445-456.
Microbiology, Immunology & Cell Biology
Research in the laboratory is focused on the involvement of interleukin (IL)-27 in host immune responses to bacterial infections. IL-27 was first identified as a factor that aids in the initiation of T cell responses and interferon-g production. However, since that time a great deal of evidence has also highlighted immune suppressive activity that is ascribed to IL-27 toward a variety of cell types. Our laboratory predominantly investigates IL-27 as a limiting factor in protective responses during infection and vaccination. This theme is integrated into several well-established projects.
The first seeks to understand how IL-27 may contribute to limitations in neonatal and infant immunity. Infections are a major contributor to early life mortality and a number of functional differences have been identified between infant and adult immune cells. We have shown IL-27 to be expressed at an elevated level in neonates and infants as compared with adults. Ongoing studies seek to understand molecular mechanisms that operate to control different levels of IL-27 expression in different age groups. The laboratory is also exploring the consequence of elevated levels of IL-27 in early life immunity with the overarching hypothesis that IL-27 suppresses protective immunity and opposes bacterial clearance during neonatal infection. We have established a neonatal mouse model of gram-negative sepsis in which we explore the influence of IL-27 on infection-related mortality, bacterial clearance, and cell-mediated immune responses. This model replicates several features of human disease, including respiratory distress and bacterial dissemination to the central nervous system.
A second area of research focus involves human macrophage and dendritic cell (DC) responses to infection by Mycobacterium tuberculosis (Mtb). Tuberculosis is a disease that remains a major threat to global public health. The severity of the epidemic has been intensified by the frequency of coinfection with HIV in developing nations and the emergence of multidrug resistant strains. Numerous cytokines have been shown to play important roles regulating adaptive immune responses to Mtb. The long-term objective of this research is to understand the involvement of IL-27 in human macrophage and dendritic cell responses to mycobacteria and the impact of these responses on the complete immune response. This is important during active infection and in the context of vaccination. The underlying hypothesis is that macrophage and DC responses to IL-27 have important implications in controlling bacterial growth as well as in directing the progression and effectiveness of the immune response to Mtb. Human macrophages express, secrete, and respond to IL-27 during infection by Mtb and the live vaccine strain, BCG. Macrophage responses to both bacteria are improved when IL-27 is neutralized. Under these conditions, the proinflammatory response is elevated and the mycobacterial recovery is significantly reduced. Recent studies have examined the macrophage intracellular environment and effector functions. My laboratory has demonstrated that IL-27 negatively regulates lysosomal acidification. IL-27 also blocks recruitment of intracellular molecules that allow for progression of the phagosome to lysosomes. Consequently, neutralization of IL-27 during infection results in increased colocalization of mycobacteria with host lysosomes. Since antigens that are processed through this pathway associate with MHC class II for surface presentation, this has important implications in the induction of adaptive immunity. We are testing this idea using primary human cells and a neonatal mouse model of vaccination and aerosol challenge.
Lastly, in collaboration with other colleagues, we are investigating the impact of opioid exposure during pregnancy on the neonatal immune response. Neonatal opioid withdrawal syndrome (NOWS) is defined as a postnatal opioid withdrawal condition that develops in neonates when a mother is addicted to, or in some cases, treated with opioids during pregnancy. We are in the midst of an opioid epidemic across the U.S., as well as right here in West Virginia, and there is a major void in understanding the impact of in utero opioid exposure on immunological responses and subsequent risk of infectious disease sequelae. Our research seeks to fill this important knowledge gap.