The prevalence of smoking habits is much higher in US veterans (21.6%) than that in the general population (13.7%). Individuals who smoke are more susceptible to influenza virus infection (Flu), which often progresses to severe acute lung injury (ALI), results in high morbidity and mortality than nonsmokers. However, the immune mechanisms by which cigarette smoke (CS) enhances Flu severity need to be better defined, and thus effective therapies are limited. To investigate this, we have established a two-hit model of 4-week CS exposure and subsequent intranasal influenza A virus (IAV)-infection (CS+Flu). In this model, by using intravital (in vivo) multi-photon-excitation fluorescence microscopy, for the first time, we observe that prior CS exposure induces hyperactivation of innate immune responses against Flu as evidenced by a significant increase in platelet-rich neutrophil-platelet aggregates (NPAs) and circulating neutrophil extracellular traps (NETs), leading to more profound weight loss and severe ALI relative to Flu alone. Our preliminary findings revealed that two-hit (CS+Flu) induces “platelet-rich” NPA formation and uniquely upregulates TLR7 (toll-like receptor 7, a sensor of single-stranded RNA of IAV) and caspase-11 (the effector of non-canonical inflammasome pathway) in circulating platelets of mice. Further, circulating neutrophils isolated from mice exposed to CS+Flu uniquely expressed the active forms of both caspase-11 and gastermin-D (GSDMD-NT), an executor of pyroptosis. Additionally, coagulation (tissue factor [TF] expression and fibrin deposition) was increased in the lung of CS+Flu relative to RA+Flu mice. These findings form the basis for our overarching hypothesis that prior CS exposure exacerbates Flu-induced ALI through pulmonary microvascular occlusion by platelet caspase-11 mediated platelet-rich NPAs, leading to GSDMD-mediated NETs generation, followed by fibrin deposition in the lung. This proposed study will be the first to introduce a novel paradigm that occlusion of lung microvasculature by platelet-rich NPAs promotes CS-induced Flu severity and potentially identify a new therapeutic target – platelet- neutrophil caspase signaling to promote Flu-induced thrombo-inflammation and severe ALI.