Antibody Treatment against Angiopoietin-Like 4 Reduces Pulmonary Edema and Injury in Secondary Pneumococcal Pneumonia

Abstract

Secondary bacterial lung infection by Streptococcus pneumoniae (S. pneumoniae) poses a serious health concern, especially in developing countries. We posit that the emergence of multiantibiotic-resistant strains will jeopardize current treatments in these regions. Deaths arising from secondary infections are more often associated with acute lung injury, a common consequence of hypercytokinemia, than with the infection per se. Given that secondary bacterial pneumonia often has a poor prognosis, newer approaches to improve treatment outcomes are urgently needed to reduce the high levels of morbidity and mortality. Using a sequential dual-infection mouse model of secondary bacterial lung infection, we show that host-directed therapy via immunoneutralization of the angiopoietin-like 4 c-isoform (cANGPTL4) reduced pulmonary edema and damage in infected mice. RNA sequencing analysis revealed that anti-cANGPTL4 treatment improved immune and coagulation functions and reduced internal bleeding and edema. Importantly, anti-cANGPTL4 antibody, when used concurrently with either conventional antibiotics or antipneumolysin antibody, prolonged the median survival of mice compared to monotherapy. Anti-cANGPTL4 treatment enhanced immune cell phagocytosis of bacteria while restricting excessive inflammation. This modification of immune responses improved the disease outcomes of secondary pneumococcal pneumonia. Taken together, our study emphasizes that host-directed therapeutic strategies are viable adjuncts to standard antimicrobial treatments. IMPORTANCE Despite extensive global efforts, secondary bacterial pneumonia still represents a major cause of death in developing countries and is an important cause of long-term functional disability arising from lung tissue damage. Newer approaches to improving treatment outcomes are needed to reduce the significant morbidity and mortality caused by infectious diseases. Our study, using an experimental mouse model of secondary S. pneumoniae infection, shows that a multimodal treatment that concurrently targets host and pathogen factors improved lung tissue integrity and extended the median survival time of infected mice. The immunoneutralization of host protein cANGPTL4 reduced the severity of pulmonary edema and damage. We show that host-directed therapeutic strategies as well as neutralizing antibodies against pathogen virulence factors are viable adjuncts to standard antimicrobial treatments such as antibiotics. In view of their different modes of action compared to antibiotics, concurrent immunotherapies using antibodies are potentially efficacious against secondary pneumococcal pneumonia caused by antibiotic-resistant pathogens.

Pericyte-Like Cells Undergo Transcriptional Reprogramming and Distinct Functional Adaptations in Acute Lung Injury

“…An examination of human lung tissue samples from the 1918 and 2009 influenza pandemics revealed that angiopoietinlike 4 was one of the most highly upregulated genes in the lung (13). Moreover, published reports suggest antagonism of cANGPTL4 in pulmonary infection models ameliorated pulmonary vascular leak and damage (14,15). In our study, we observed significant upregulation of Angptl4 in pericyte-like cells both ex vivo and in vivo following stimulation.…”

Pericyte‐like cells undergo transcriptional reprogramming and distinct functional adaptations in acute lung injury

“…An examination of human lung tissue samples from the 1918 and 2009 influenza pandemics revealed that angiopoietin‐like 4 was one of the most highly upregulated genes in the lung 30 . Published reports suggest antagonism of cANGPTL4 in pulmonary infection models ameliorated pulmonary vascular leak and damage 25,31 …”

Neutrophil extracellular traps induced by IL-8 aggravate atherosclerosis via activation NF-κB signaling in macrophages

“…For example, Hu et al [19] demonstrated that LPS-induced NETs significantly upregulated the production of IL-1β from macrophages. A recent study suggested that adultonset Still's disease (AOSD) neutrophils released NETs to exert a potent capacity to accelerate the activation of pro-inflammatory macrophages and increased the expression of IL-1β, IL-6, and tumor necrosis factor (TNF)-α [20]. In line with previous studies, our results indicated that PMA, a potent NET activator, triggered neutrophils to release NETs, which in turn stimulated the production of proinflammatory cytokines IL-8, IL-6 and IL-1β from macrophages by upregulating TLR9 mRNA expression.…”