CXCL17 Is a Specific Diagnostic Biomarker for Severe Pandemic Influenza A(H1N1) That Predicts Poor Clinical Outcome

Abstract

The C-X-C motif chemokine ligand 17 (CXCL17) is chemotactic for myeloid cells, exhibits bactericidal activity, and exerts anti-viral functions. This chemokine is constitutively expressed in the respiratory tract, suggesting a role in lung defenses. However, little is known about the participation of CXCL17 against relevant respiratory pathogens in humans. Here, we evaluated the serum levels and lung tissue expression pattern of CXCL17 in a cohort of patients with severe pandemic influenza A(H1N1) from Mexico City. Peripheral blood samples obtained on admission and seven days after hospitalization were processed for determinations of serum CXCL17 levels by enzyme-linked immunosorbent assay (ELISA). The expression of CXCL17 was assessed by immunohistochemistry (IHQ) in lung autopsy specimens from patients that succumbed to the disease. Serum CXCL17 levels were also analyzed in two additional comparative cohorts of coronavirus disease 2019 (COVID-19) and pulmonary tuberculosis (TB) patients. Additionally, the expression of CXCL17 was tested in lung autopsy specimens from COVID-19 patients. A total of 122 patients were enrolled in the study, from which 68 had pandemic influenza A(H1N1), 24 had COVID-19, and 30 with PTB. CXCL17 was detected in post-mortem lung specimens from patients that died of pandemic influenza A(H1N1) and COVID-19. Interestingly, serum levels of CXCL17 were increased only in patients with pandemic influenza A(H1N1), but not COVID-19 and PTB. CXCL17 not only differentiated pandemic influenza A(H1N1) from other respiratory infections but showed prognostic value for influenza-associated mortality and renal failure in machine-learning algorithms and regression analyses. Using cell culture assays, we also identified that human alveolar A549 cells and peripheral blood monocyte-derived macrophages increase their CXCL17 production capacity after influenza A(H1N1) pdm09 virus infection. Our results for the first time demonstrate an induction of CXCL17 specifically during pandemic influenza A(H1N1), but not COVID-19 and PTB in humans. These findings could be of great utility to differentiate influenza and COVID-19 and to predict poor prognosis specially at settings of high incidence of pandemic A(H1N1). Future studies on the role of CXCL17 not only in severe pandemic influenza, but also in seasonal influenza, COVID-19, and PTB are required to validate our results.

CXCL17 is an endogenous inhibitor of CXCR4 via a novel mechanism of action

“…In vivo , endogenous CXCR4 inhibitors may represent an important regulatory mechanism to prevent excessive receptor activation. Notably CXCL17 expression can reach ~ 60 ng/ml in vitro while serum CXCL17 concentrations can reach ~ 5 ng/ml during influenza infection 10 . Since CXCL17 expression is highly localised to secretory cells in mucosal tissue 39 it is plausible that CXCL17 expression reaches concentrations sufficient to inhibit CXCR4.…”

“…In addition, CXCL17 has antimicrobial properties at high concentrations 5 and modulates angiogenesis 4,6 . CXCL17 has also been implicated in several pathologies including breast 7 and hepatocellular cancers 8 , as well as inflammatory lung pathologies such as idiopathic pulmonary fibrosis 5 , asthma 9 , influenza 10 and SARS-CoV-2 11 infection. Despite mediating a wide range of important functional responses, the receptor(s) for CXCL17 are still unknown.…”

Differential Leukocyte Expression of IFITM1 and IFITM3 in Patients with Severe Pandemic Influenza A(H1N1) and COVID-19

“…We recruited 31 consecutive individuals with severe pandemic influenza A(H1N1) from a previously reported cohort (Choreño-Parra and others 2021c , 2021d ). Patients attending with acute respiratory distress syndrome (ARDS), who required intensive care unit admission and mechanical ventilation (MV), were eligible for this study if they provided adequate samples for analysis and met the inclusion criteria described before (Choreño-Parra and others 2021c , 2021d ). Data and specimens from a comparative cohort of age- and sex-matched HC ( n = 8) and patients with severe COVID-19 ( n = 16) were also included in the following analyses.…”

A comprehensive review of chemokine CXC17 (VCC1) in cancer, infection, and inflammation

“…Notably, investigations of CXCL17 serum levels in patients with influenza A (H1N1) found that elevated CXCL17 levels were associated with a bad prognosis, leading to kidney damage and death. After in vitro infection with the influenza A (H1N1) pdm09 virus, human alveolar A549 cells and peripheral blood monocyte‐derived macrophages are thought to generate CXCL17 (Choreño‐Parra, Jiménez‐Álvarez, et al, 2021). Due to the convergence of influenza and COVID‐19, which is expected to be one of the most serious public health crises in recent history, these data might aid clinical decision‐making during the flu season.…”