Neutrophils regulate the lung inflammatory response via γδ T cell infiltration in an experimental mouse model of human metapneumovirus infection

Abstract

Neutrophils are the most abundant leukocytes in human circulation. They are the first immune cell population recruited to the sites of infection. However, the role of neutrophils to regulate host immune responses during respiratory viral infections is largely unknown. To elucidate the role of neutrophils in respiratory antiviral defense, we used an experimental mouse model of human metapneumovirus (HMPV) infection. HMPV, a member of the family, is a leading respiratory pathogen causing severe symptoms, such as bronchiolitis and pneumonia, in young, elderly, and immunocompromised patients. We demonstrate that neutrophils are the predominant population of immune cells recruited into the lungs after HMPV infection. This led us to hypothesize that neutrophils represent a key player of the immune response during HMPV infection, thereby regulating HMPV-induced lung pathogenesis. Specific depletion of neutrophils in vivo using a mAb and simultaneous infection with HMPV exhibited higher levels of inflammatory cytokines, pulmonary inflammation, and severe clinical disease compared with HMPV-infected, competent mice. Interestingly, the lack of neutrophils altered γδ T cell accumulation in the lung. The absence of γδ T cells during HMPV infection led to reduced pulmonary inflammation. These novel findings demonstrate that neutrophils play a critical role in controlling HMPV-induced inflammatory responses by regulating γδ T cell infiltration to the site of infection.

Human Metapneumovirus Attachment Protein Contributes to Neutrophil Recruitment into the Airways of Infected Mice

“…To determine whether the HMPV attachment glycoprotein plays a role in the recruitment of neutrophils, BAL samples were collected 24 h after inoculating mice with rHMPV, rHMPV-∆G or PBS, and differential cell analysis was performed. We focused on the neutrophil recruitment at 24 h based on previous observations that indicate that neutrophil recruitment peaks at day 1 after HMPV infection [ 20 ]. As shown in Figure 2 a, analyses of cytospin preparations revealed a significant decrease in the total number of neutrophils recruited to alveolar spaces in mice infected with rHMPV-ΔG (1.0 × 10 5 ± 0.2) when compared with those with rHMPV infection (3.1 × 10 5 ± 0.3), indicating that G protein contributes to the recruitment of neutrophils.…”

“…Mice were euthanized by intraperitoneal injection of ketamine and xylazine, and exsanguinated via the femoral vessels, as previously described [ 20 , 28 ]. Bronchalveolar lavage (BAL) samples were collected by flushing the lungs twice with 1 mL PBS and centrifuged 3500 rpm for 5 min at 4 °C.…”

“…Clinical evidence indicates that HMPV induces neutrophil infiltration and associated mediators within the airways of infants with bronchiolitis [ 17 ], providing evidence of the neutrophilic inflammatory response in vivo and highlighting the importance of these cells as a potential target of therapeutic intervention for treatment of bronchiolitis in infected children. The increased neutrophil infiltration by HMPV in the airways has been reproduced in the mouse model of infection, including in adult [ 18 , 19 , 20 ] and aged mice [ 21 ], where HMPV infection induces similar neutrophil recruitment into the airways of both age groups of mice [ 21 ]. However, the role of HMPV in regulating the recruitment of neutrophils to the lungs remains elusive.…”

Вплив Відновлювального Лікування На Імунний Статус Дітей Із Рекурентними Респіраторними Захворюваннями

“…Такі зміни здатні порушувати адекватну імунну відпо-відь, що може сприяти затяжному перебігу та хро-нізації патологічного процесу в цього контингенту дітей і вимагає проведення відновлювального ліку-вання [12,13].…”

Influence of recovery treatment based on the haloaerosoltherapy upon non-specific defense of children with recurrent respiratory diseases

“…Зважаючи на важливу роль імунної системи, яка в період дитинства лише проходить своє становлення, особливу увагу слід приділяти оцінці змін показників неспецифічного захисту, який визначає першу лінію захисту від інфекційних агентів [8,11,18]. Дослідження різних авторів вказують на наявність у дітей з частими ГРЗ змін з боку макрофагальної ланки імунітету [2,11,13], які можуть зберігатися навіть після стихання гострих явищ.…”