Hypercapnia Suppresses Macrophage Antiviral Activity and Increases Mortality of Influenza A Infection via Akt1

Abstract

Hypercapnia, elevation of the partial pressure of CO2 in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. We previously showed that hypercapnia inhibits multiple macrophage and neutrophil antimicrobial functions, and that it increases the mortality of bacterial pneumonia in mice. Here, we show that normoxic hypercapnia increases viral replication, lung injury and mortality in mice infected with influenza A virus (IAV). Elevated CO2 increased IAV replication and inhibited antiviral gene and protein expression in macrophages in vivo and in vitro. Hypercapnia potentiated IAV-induced activation of Akt, while specific pharmacologic inhibition or shRNA knockdown of Akt1 in alveolar macrophages blocked hypercapnia's effects on IAV growth and the macrophage antiviral response. Our findings suggest that targeting Akt1 or downstream pathways through which elevated CO2 signals could enhance macrophage antiviral host defense and improve clinical outcomes in hypercapnic patients with advanced lung disease.

Hypercapnia in the critically ill: insights from the bench to the bedside

“…A further study by Casalino-Matsuda et al . described the effects of elevated CO 2 on alveolar macrophages in an influenza A virus (IAV) model [9]. HC increased IAV replication and inhibited antiviral gene and protein expression in macrophages both in vivo and in vitro through activation of protein kinase B [9].…”

Carbon dioxide detection in biological systems

“…These two reviews are built upon by research by Casalino-Matsuda et al [12] investigating the LPS-induced changes in innate immunity and DNA replication-related gene transcription in the macrophage. Recent studies have demonstrated that HC can inhibit select innate immune responses.…”

Hypercapnia: An Aggravating Factor in Asthma

“…In mice exposed to normoxic hypercapnia, high CO 2 levels decreased IL-6 and TNF expression in the lung during the early phase of Pseudomonas aeruginosa infection, and inhibited the phagocytosis of bacteria and generation of reactive oxygen species by lung neutrophils, resulting in increased burden of Pseudomonas aeruginosa in the lungs and other organs and higher mortality [ 25 ]. More recently, Casalino-Matsuda et al, has reported that hypercapnia increased virus-induced lung injury and mortality in mice infected with influenza A virus and hypercapnia [ 29 ]. They observed that elevated CO 2 levels increased influenza A virus replication and inhibited antiviral gene and protein expression in macrophages.…”

“…They observed that elevated CO 2 levels increased influenza A virus replication and inhibited antiviral gene and protein expression in macrophages. Interestingly, both in vivo studies showed similar reversibility of hypercapnia-induced defects in antiviral and antibacterial immunity [ 25 , 29 ]. There have been several reports suggesting that hypercapnia activates the renin-angiotensin system and angiotensin-converting enzyme 2 (ACE2) expression [ 116 , 117 , 118 ], which is identified as a receptor for the spike protein of SARS-CoV-2 and facilitating the viral entry into target cells [ 118 ].…”

“…The lower tidal volumes during protective ventilation can lead to hypercapnia and an associated drop in pH resulting in hypercapnic respiratory acidosis that has been reported as a protective effect via the inhibition of the nuclear factor-κB (NF-κB) pathway, a pivotal transcription activator in inflammation and injury [ 7 , 22 ]. However, in recent years, it has become increasingly evident that elevated CO 2 acts as a gaso-signaling molecule, resulting in deleterious effects in various organs such as the lung [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ] and skeletal muscles [ 30 , 31 , 32 ] as well as innate immunity system [ 25 , 29 , 33 , 34 , 35 , 36 , 37 ]. In the lung, recent studies reported that high levels of CO 2 activate specific gene expression [ 26 , 38 , 39 , 40 ] and signal transduction pathways with adverse consequences on alveolar fluid clearance through Na, K-ATPase endocytosis via intracellular calcium- or extracellular signal-regulated kinase (ERK)-mediated AMP-activated protein kinase (AMPK)/protein kinase C-ζ/c-Jun-N-Terminal Kinase (JNK) signaling or soluble adenylyl cyclase-mediated protein kinase A-Iα signaling [ 24 , 41 , 42 , 43 , 44 , 45 , 46 ] and epithelial cell repair via AMPK-mediated Rac1-GTPase signaling, NF-κB pathways or miR-183-regulated mitochondrial dysfunction [ 28 , 47 , 48 , 49 ].…”