Date Published: September 2, 2016
Publisher: Public Library of Science
Author(s): Heba H. Mostafa, Peter Vogel, Ashok Srinivasan, Charles J. Russell, Kanta Subbarao.
In immunocompromised patients, parainfluenza virus (PIV) infections have an increased potential to spread to the lower respiratory tract (LRT), resulting in increased morbidity and mortality. Understanding the immunologic defects that facilitate viral spread to the LRT will help in developing better management protocols. In this study, we immunosuppressed mice with dexamethasone and/or cyclophosphamide then monitored the spread of viral infection into the LRT by using a noninvasive bioluminescence imaging system and a reporter Sendai virus (murine PIV type 1). Our results show that immunosuppression led to delayed viral clearance and increased viral loads in the lungs. After cessation of cyclophosphamide treatment, viral clearance occurred before the generation of Sendai-specific antibody responses and coincided with rebounds in neutrophils, T lymphocytes, and natural killer (NK) cells. Neutrophil suppression using anti-Ly6G antibody had no effect on infection clearance, NK-cell suppression using anti-NK antibody delayed clearance, and T-cell suppression using anti-CD3 antibody resulted in no clearance (chronic infection). Therapeutic use of hematopoietic growth factors G-CSF and GM-CSF had no effect on clearance of infection. In contrast, treatment with Sendai virus—specific polysera or a monoclonal antibody limited viral spread into the lungs and accelerated clearance. Overall, noninvasive bioluminescence was shown to be a useful tool to study respiratory viral progression, revealing roles for NK and T cells, but not neutrophils, in Sendai virus clearance after treatment with dexamethasone and cyclophosphamide. Virus-specific antibodies appear to have therapeutic potential.
Paramyxoviruses are responsible for approximately half of all respiratory viral—related hospitalizations of children in the United States , and they cause high levels of morbidity and mortality in immunocompromised patients of any age [2, 3]. These viruses include human respiratory syncytial virus (RSV), human metapneumovirus, and the human parainfluenza viruses (HPIVs). This study focuses on the PIVs. HPIV1 is the leading cause of severe croup (laryngotracheobronchitis), and HPIV3 is a leading cause of bronchiolitis and pneumonia [4–6]. There are no licensed vaccines or other therapeutic agents against these viruses, yet nearly all children become infected with them by the age of 5 years .
In this work, we studied the dynamics of SeV spread and clearance in pharmacologically immunosuppressed mice and subsequently evaluated immunotherapy strategies aimed at supplanting the components that function during the normal host response but were lacking in the immunosuppressed animals. In humans, both lymphopenia and neutropenia are associated with an increased risk or progression of parainfluenza and other respiratory viral infections to the LRT, and these conditions increase the risk of mortality [2, 10]. The contributory effect of a decrease in the lymphocyte or neutrophil count is unknown. It is unclear if increasing the neutrophil count by administering G-CSF to patients will mitigate this risk. The role of NK cells in viral clearance in unknown. The role of the antibody-mediated protective effect after intravenous immunoglobulin (Ig) is administered to patients with LRT involvement is also unclear, and it is impractical to study it in humans because of confounding variables.