A Systemic Neutrophil Response Precedes Robust CD8⁺T-Cell Activation during Natural Respiratory Syncytial Virus Infection in Infants

Abstract

Severe primary respiratory syncytial virus (RSV) infections are characterized by bronchiolitis accompanied by wheezing. Controversy exists as to whether infants suffer from virus-induced lung pathology or from excessive immune responses. Furthermore, detailed knowledge about the development of primary T-cell responses to viral infections in infants is lacking. We studied the dynamics of innate neutrophil and adaptive T-cell responses in peripheral blood in relation to theviral load and parameters of disease in infants admitted to the intensive care unit with severe RSV infection. Analysis of primary T-cell responses showed substantial CD8 ؉ T-cell activation, which peaked during convalescence. A strong neutrophil response, characterized by mobilization of bone marrow-derived neutrophil precursors, preceded the peak in T-cell activation. The kinetics of this neutrophil response followed the peak of clinical symptoms and the viral load with a 2-to 3-day delay. From the sequence of events, we conclude that CD8 ؉ T-cell responses, initiated during primary RSV infections, are unlikely to contribute to disease when it is most severe. The mobilization of precursor neutrophils might reflect the strong neutrophil influx into the airways, which is a characteristic feature during RSV infections and might be an integral pathogenic process in the disease.

Serum Antibodies Critically Affect Virus-Specific CD4+/CD8+ T Cell Balance during Respiratory Syncytial Virus Infections

“…Similar to our observations, this group found significantly higher ratios for IFN-g-producing CD4 + /CD8 + T cells specific for RSV than for influenza virus in both young and elderly groups. In contrast, during severe primary RSV infections, CD8 + T cell responses dominate during the acute response (50). Because the immune status during the first year after primary infection and before a secondary RSV exposure has not been monitored, it is currently not clear whether a shift in the CD4 + /CD8 + memory T cell ratio results from an ineffective differentiation or poor survival of RSV-specific CD8 + memory T cells.…”

Airway CD8+T Cells Are Associated with Lung Injury during Infant Viral Respiratory Tract Infection

“…The neutrophil content in the airways remained constant over the course of mechanical ventilation in both uninfected (median, 51% of airway cells; range, 18-85%) and infected (median, 48% of airway cells; range, 5-86%) patients ( Figure 2A); however, the median absolute neutrophil count (ANC) in blood varied significantly between uninfected and infected groups at initiation of mechanical ventilation (8,318 cells/ml, range, 4176-12931 versus 3,815 cells/ml, range, 820-14994; P = 0.005) and over the study period as a whole (6,350 cells/ml versus 4,874 cells/ml; P = 0.02) (Figure 2A). This change in circulating neutrophils could be due to an influx of neutrophils into the airway of infected patients (20,21). Neutropenia (ANC , 1,500 cells/ml) occurred in only 6 out of the 178 clinical complete blood counts (RSV-infected [n = 5] and HMPV-infected [n = 1] patients) with no subject having severe neutropenia (ANC , 500 cells/ml).…”

Host response to mechanical ventilation for viral respiratory tract infection

“…RSV pathogenesis is not completely understood. In humans, severe RSV infection results in a predominantly neutrophil infiltrate in bronchoalveolar lavage fluid (BALF) [6] and a strong innate pro-inflammatory response, reflected by exhaustion of the peripheral blood neutrophil pool after peak values of viral load and disease severity [7]. In mice, the innate immune response is characterised by induction of type I interferon (IFN)-regulated genes and chemokine genes, and genes involved in inflammation and antigen processing [8].…”