Rapid control of pandemic H1N1 influenza by targeting NKT-cells

Abstract

Swine influenza A viruses (IAV) are a major cause of respiratory disease in pigs and humans. Currently approved anti-influenza therapies directly target the virus, but these approaches are losing effectiveness as new viral strains quickly develop drug resistance. To over come this challenge, there is an urgent need for more effective antiviral drugs. Here we tested the anti-influenza efficacy of the invariant natural killer T (NKT) cell superagonist, α-galactosylceramide (α-GalCer), which stimulates a wide array of anti-viral immune responses. We show that intranasal but not systemic administration of α-GalCer to piglets infected with pandemic A/California/04/2009 (CA04) H1N1 IAV ameliorated disease symptoms and resulted in the restoration of weight gain to the level of uninfected pigs. Correspondingly, viral titers in the upper-and lower-respiratory tract were reduced only in piglets that had received intranasal α-GalCer. Most significantly, lung inflammation as a consequence of virus persistence was largely prevented when NKT-cells were targeted via the respiratory route. Thus, targeting mucosal NKT-cells may provide a novel and potent platform for improving the course of disease in swine infected with seasonal and pandemic influenza viruses, and leads to the suggestion that this may also be true in humans and therefore deserves further study.

Next Generation Sequencing of the Pig αβ TCR Repertoire Identifies the Porcine Invariant NKT Cell Receptor

“…The addition of exogenous cytokines was not required to expand pig iNKT cells, which is consistent with a previous report (23). iNKT cells were identified using anti-porcine CD3ε Ab and mCD1d tetramer loaded with the a-GalCer analogue PBS57, which cross-reacts with the porcine invariant TCR (22,24,25,(32)(33)(34)(35). iNKT cells and Tconv were, respectively, distinguished as CD3ε + CD1d tetramer + and CD3ε + CD1d tetramer 2 cells.…”

“…Thus, pigs may be useful for determining the efficacy of various glycolipid ligands for human use. There is also potential to use iNKT cell agonists for veterinary applications, including as vaccine adjuvants and antimicrobial agents, which has recently been explored in swine with encouraging results (25,(33)(34)(35).…”

New IT driven rapid manufacturing for emergency response

“…It mainly includes outbreaks of pandemic [ 10 ] (e.g., COVID-19, Middle East Respiratory Syndrome (MERS), SARS, H1N1, smallpox, pestis, etc. ), animal pandemics (e.g., foot-and-mouth disease [ 11 ], avian influenza [ 12 ], swine influenza [ 13 ], etc. ), group unexplained diseases, and other events that seriously affect public health and life safety.…”

Harnessing Invariant NKT Cells to Improve Influenza Vaccines: A Pig Perspective

“…In contrast, mice express two copies of CD1d, but lack the other CD1 genes [ 54 ]. Porcine CD1d is highly homologous to mouse and human CD1d to the extent that fluorescently labeled mouse or human tetramers loaded with α-GalCer analogs can be used with equal efficiency to visualize pig iNKT cells by flow cytometry [ 19 , 51 , 55 , 56 , 57 , 58 , 59 ]. We have used this tool to show that the prevalence and distribution of iNKT cells among outbred pigs is more like humans than like mice, with the frequency of iNKT cells in blood, spleen, lung, liver, bronchoalveolar lavage fluid (BALF), tracheobronchial lymph node (TBLN), cervical lymph nodes (CLN), and mesenteric lymph nodes (MLN) typically between 0.01% and 1% of total lymphocytes [ 19 , 60 ].…”