Emma Hornick

The Contributions of NLRs to Pathogenic and Protective Immune Responses during Influenza Virus Infection
Biography

Nucleotide-binding domain and leucine-rich-repeat-containing receptors (NLRs) are a family of cytosolic pattern recognition receptors with a range of functions including: pathogen/damage sensing, modulation of inflammatory signaling, and transcriptional control of genes controlling antigen presentation and processing. In response to PAMPs and DAMPs, some NLRs form multi-protein complexes known as inflammasomes, consisting of an NLR, the adaptor protein ASC, and caspase-1. Activation of inflammasomes results in caspase-1-mediated processing of pro-IL-1β and pro-IL-18 into their mature forms, which can be secreted. Inflammasome activation can also drive a pro-inflammatory form of cell death called pyroptosis.

NLRs have been implicated in the response to a number of viruses including influenza A virus (IAV). Influenza A virus represents an ongoing public health concern, infecting between 5-20% of the US population annually. The number and severity of infections can rise dramatically in years when strains emerge to which there is little pre-existing immunity within the population. Both innate and adaptive immune responses contribute to pathogen clearance and tissue damage during IAV infection, thus understanding the factors that initiate and influence these responses, including signaling downstream of viral sensing by pattern recognition receptors, is important. The NLRP3 inflammasome and other members of the NLR family shape both innate and adaptive responses to IAV. Activation of the NLRP3 inflammasome during IAV infection can be triggered by at least three stimuli: single-stranded viral RNA, H+ flux through the IAV-encoded M2 ion channel, and aggregates of the IAV virulence factor PB1-F2. Mice lacking either NLRP3 or caspase-1 exhibit higher mortality and compromised inflammatory cytokine production and cellular recruitment to the lungs.

To determine whether other NLRs are involved in the immune response to IAV infection, we infected multiple NLR-deficient mouse strains with IAV and tracked morbidity and mortality. Our findings from this initial screen indicate NLRC4 and NLRP12 have previously unappreciated roles during IAV infection. Elucidating the mechanisms by which they afford protection and/or mediate disease is the focus of our ongoing studies.

Hornick EE, Banoth B, Miller AM, Zacharias ZR, Jain N, Wilson ME, Gibson-Corley KN, Legge KL, Bishop GA, Sutterwala FS, Cassel SL. Nlrp12 Mediates Adverse Neutrophil Recruitment during Influenza Virus Infection. J Immunol. 2018 Feb 1;200(3):1188-1197. doi: 10.4049/jimmunol.1700999. Epub 2017 Dec 27. PubMed PMID: 29282312; PubMed Central PMCID: PMC5831365.

Ulland TK, Jain N, Hornick EE, Elliott EI, Clay GC, Sadler JJ, Mills KAM, Janowski AM, Volk APD, Wang K, Legge KL, Gakhar L, Bourdi M, Ferguson PJ, Wilson ME, Cassel SL, Sutterwala FS. Nlrp12 mutation in C57Bl/6J mice results in a substrain-specific defect in neutrophil recruitment. Nat Comm. 2016; 7:13180.

Janowski AM, Colegio OR, Hornick EE, McNiff JM, Martin MD, Badovinac VP, Norian LA, Zhang W, Cassel SL, Sutterwala FS. NLRC4 suppresses melanoma tumor progression independently of inflammasome activation. J Clin Invest. 2016; 126(10):3917-3928.

Uc A, Olivier AK, Griffin MA, Meyerholz DK, Yao J, Abu-El-Haija M, Buchanan KM, Vanegas-Calderon OG, Abu-El-Haija M, Pezzulo AA, Reznikov LR, Hoegger MJ, Rector MV, Ostedgaard LS, Taft PJ, Gansemer ND, Ludwig PS, Hornick EE, Stoltz DA, Ode KL, Welsh MJ, Engelhardt JF, Norris AW. Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass. Clin Sci. 2015; 128(2):131-42.

Caraballo JC, Borcherding J, Rector M, Hornick E, Stoltz D, Zabner J, Comellas AP. Role of PON in anoxia-reoxygenation injury: a Drosophila melanogaster transgenic model. PLoS One. 2014; 9(1):e84434

Stoltz DA, Rokhlina T, Ernst SE, Pezzulo AA, Ostedgaard LS, Karp PH, Samuel MS, Reznikov LR, Rector MV, Gansemer ND, Bouzek DC, Abou Alaiwa MH, Hoegger MJ, Ludwig PS, Taft PJ, Wallen TJ, Wohlford-Lenane C, McMenimen JD, Chen JH, Bogan KL, Adam RJ, Hornick EE, Nelson GA 4th, Hoffman EA, Chang EH, Zabner J, McCray PB Jr, Prather RS, Meyerholz DK, Welsh MJ. Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs. J Clin Invest. 2013; 123(6):2685-93.

Pezzulo AA, Hornick EE, Rector MV, Estin M, Reisetter AC, Taft PJ, Butcher SC, Carter AB, Manak JR, Stoltz DA, Zabner J. Expression of human paraoxonase 1 decreases superoxide levels and alters bacterial colonization in the gut of Drosophila melanogaster. PLoS One. 2012;7(8):e43777

Ostedgaard LS, Meyerholz DK, Chen JH, Pezzulo AA, Karp PH, Rokhlina T, Ernst SE, Hanfland RA, Reznikov LR, Ludwig PS, Rogan MP, Davis GJ, Dohrn CL, Wohlford-Lenane C, Taft PJ, Rector MV, Hornick E, Nassar BS, Samuel M, Zhang Y, Richter SS, Uc A, Shilyansky J, Prather RS, McCray PB Jr, Zabner J, Welsh MJ, Stoltz DA. The ΔF508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigs. Sci Transl Med. 2011;3(74):74ra24.

Stoltz DA, Meyerholz DK, Pezzulo AA, Ramachandran S, Rogan MP, Davis GJ, Hanfland RA, Wohlford-Lenane C, Dohrn CL, Bartlett JA, Nelson GA 4th, Chang EH, Taft PJ, Ludwig PS, Estin M, Hornick EE, Launspach JL, Samuel M, Rokhlina T, Karp PH, Ostedgaard LS, Uc A, Starner TD, Horswill AR, Brogden KA, Prather RS, Richter SS, Shilyansky J, McCray PB Jr, Zabner J, Welsh MJ. Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth. Sci Transl Med. 2010 Apr 28;2(29):29ra31.

Pinto BS, Wilmington SR, Hornick EE, Wallrath LL, Geyer PK. Tissue-specific defects are caused by loss of the Drosophila MAN1 LEM domain protein. Genetics. 2008;180(1)133-45.

Postdoctoral Associate
Microbiology and Immunology
University of Iowa
Emma Hornick