Acute lower respiratory tract infections cause a terrible public health burden at present, with potential for worse in the coming years. The outcome of these infections is determined by innate immune responses (such as neutrophil recruitment and activation), necessary for host defense but also contributing to lung injury. Innate immune responses in the lungs require the coordinated expression of diverse mediators including adhesion molecules, chemokines, colony stimulating factors, and cytokines that are absent or present only at low levels in uninfected lungs, but are expressed at high levels during infection. Similar mediators are induced during most lung infections, although individual mediators can have different roles during different infections. The coordinated expression suggests programs of gene regulation. NF-kappaB transcription factors are critical to the gene expression program directing innate immunity in the lungs, with RelA inducing innate immunity genes mediating host defense and p50 counteracting this gene induction to prevent lung injury. Other transcription factors are also important, such as STAT3 which both facilitates host defense and limits lung injury. These transcription factors have cell-specific roles during infection, and elucidating unique cell-specific roles in lung innate immunity is a major ongoing effort. Finally, expression of innate immunity mediators is regulated post-transcriptionally as well. MicroRNAs target innate immunity transcripts, and miRNAs themselves are subject to modifications such as uridylation by Zcchc11 to relieve their repressive activities. An improved knowledge of the molecular mechanisms directing innate immunity in the lungs will provide new directions for preventing and curing acute lower respiratory tract infections.
- Director, Pulmonary Center, Boston University School of Medicine
- Professor, Biochemistry, Boston University School of Medicine
- Professor, Microbiology, Boston University School of Medicine
- Graduate Faculty (Primary Mentor of Grad Students), Boston University School of Medicine, Division of Graduate Medical Sciences
- Harvard School of Public Health, ScD
- Amherst College, BA
- Published on 7/15/2018
Dela Cruz CS, Wunderink RG, Christiani DC, Cormier SA, Crothers K, Doerschuk CM, Evans SE, Goldstein DR, Khatri P, Kobzik L, Kolls JK, Levy BD, Metersky ML, Niederman MS, Nusrat R, Orihuela CJ, Peyrani P, Prince AS, Ramírez JA, Ridge KM, Sethi S, Suratt BT, Sznajder JI, Tsalik EL, Walkey AJ, Yende S, Aggarwal NR, Caler EV, Mizgerd JP. Future Research Directions in Pneumonia. NHLBI Working Group Report. Am J Respir Crit Care Med. 2018 Jul 15; 198(2):256-263. PMID: 29546996.
- Published on 7/1/2018
Quinton LJ, Walkey AJ, Mizgerd JP. Integrative Physiology of Pneumonia. Physiol Rev. 2018 Jul 01; 98(3):1417-1464. PMID: 29767563.
- Published on 6/1/2018
Hartmann N, McMurtrey C, Sorensen ML, Huber ME, Kurapova R, Coleman FT, Mizgerd JP, Hildebrand W, Kronenberg M, Lewinsohn DM, Harriff MJ. Riboflavin Metabolism Variation among Clinical Isolates of Streptococcus pneumoniae Results in Differential Activation of Mucosal-associated Invariant T Cells. Am J Respir Cell Mol Biol. 2018 Jun; 58(6):767-776. PMID: 29356555.
- Published on 10/1/2017
Willinger CM, Rong J, Tanriverdi K, Courchesne PL, Huan T, Wasserman GA, Lin H, Dupuis J, Joehanes R, Jones MR, Chen G, Benjamin EJ, O'Connor GT, Mizgerd JP, Freedman JE, Larson MG, Levy D. MicroRNA Signature of Cigarette Smoking and Evidence for a Putative Causal Role of MicroRNAs in Smoking-Related Inflammation and Target Organ Damage. Circ Cardiovasc Genet. 2017 Oct; 10(5). PMID: 29030400.
- Published on 9/18/2017
Wasserman GA, Szymaniak AD, Hinds AC, Yamamoto K, Kamata H, Smith NM, Hilliard KL, Carrieri C, Labadorf AT, Quinton LJ, Ai X, Varelas X, Chen F, Mizgerd JP, Fine A, O'Carroll D, Jones MR. Expression of Piwi protein MIWI2 defines a distinct population of multiciliated cells. J Clin Invest. 2017 Oct 02; 127(10):3866-3876. PMID: 28920925.
- Published on 8/15/2017
Coleman FT, Blahna MT, Kamata H, Yamamoto K, Zabinski MC, Kramnik I, Wilson AA, Kotton DN, Quinton LJ, Jones MR, Pelton SI, Mizgerd JP. Capacity of Pneumococci to Activate Macrophage Nuclear Factor ?B: Influence on Necroptosis and Pneumonia Severity. J Infect Dis. 2017 Aug 15; 216(4):425-435. PMID: 28368460.
- Published on 7/31/2017
Kasotakis G, Galvan MD, Osathanugrah P, Dharia N, Bufe L, Breed Z, Mizgerd JP, Remick DG. Timing of valproic acid in acute lung injury: prevention is the best therapy? J Surg Res. 2017 Dec; 220:206-212. PMID: 29180183.
- Published on 6/30/2017
Kozlowski E, Wasserman GA, Morgan M, O'Carroll D, Ramirez NP, Gummuluru S, Rah JY, Gower AC, Ieong M, Quinton LJ, Mizgerd JP, Jones MR. The RNA uridyltransferase Zcchc6 is expressed in macrophages and impacts innate immune responses. PLoS One. 2017; 12(6):e0179797. PMID: 28665939.
- Published on 5/18/2017
Traber KE, Symer EM, Allen E, Kim Y, Hilliard KL, Wasserman GA, Stewart CL, Jones MR, Mizgerd JP, Quinton LJ. Myeloid-epithelial cross talk coordinates synthesis of the tissue-protective cytokine leukemia inhibitory factor during pneumonia. Am J Physiol Lung Cell Mol Physiol. 2017 Sep 01; 313(3):L548-L558. PMID: 28522567.
- Published on 5/17/2017
Smith NM, Wasserman GA, Coleman FT, Hilliard KL, Yamamoto K, Lipsitz E, Malley R, Dooms H, Jones MR, Quinton LJ, Mizgerd JP. Regionally compartmentalized resident memory T cells mediate naturally acquired protection against pneumococcal pneumonia. Mucosal Immunol. 2018 Jan; 11(1):220-235. PMID: 28513594.
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