Molecular Biology of Pneumovirus

Pneumoviruses are responsible for acute respiratory tract infections in humans and animals. Human RSV (HRSV) is the major cause of bronchiolitis of children under 2 of age worldwide. It is also responsible for acute respiratory infections in the elderly as well as in bone marrow transplant recipients. Like its human counterpart, Bovine RSV (BRSV) is the most important viral respiratory pathogen of calves and is responsible for large economic losses in European dairy and beef farming. The first vaccines for humans were commercialized only in 2023, and are dedicated to people ˃ 60 and to pregnant women. Some vaccines are commercialized for cattle, but their efficiency has still to be improved. The only treatment available for children consisted in the preventive injection of a humanized monoclonal antibody directed against the surface F glycoprotein (palivizumab Synagis®, nisrevimab). Similar to HRSV, the human metapneumovirus (HMPV) is also an important pathogen responsible for children and elderly severe respiratory infections. However, there is no treatment available to treat or prevent HMPV infections.

Pneumovirses belong to the Mononegavirales (MNV) order, which includes various human and animal pathogens like rabies, measles, mumps, Nipah, or Ebola and Marburg viruses. They are enveloped viruses with a single-strand RNA genome of negative polarity, that share similar replication mechanisms and encode for similar proteins. The viral RNA genome is encapsidated by the viral nucleoprotein N, forming a helical nucleocapsid NC. After fusion of the viral envelope with the cell membrane mediated by the F protein, the viral NC penetrates into the cytoplasm. This NC is a template for the RNA-dependent RNA polymerase (RdRp) composed of L, P (the main cofactor of L, N, and M2-1 and M2-2, which act as transcription and replication co-factors, respectively. Viral RNA synthesis is performed in cytoplasmic viral factories (also called “inclusion bodies”) that contain all the RdRp components. During their synthesis, both the nascent antigenome and the genome are encapsidated by N proteins at all steps. The neo-synthesized genome associated with N either serves as a template for secondary transcription or is assembled with matrix (M) proteins to allow budding of the neo-synthesized virions at the plasma membrane. The M protein plays a major role in viral particles assembly by interacting with plasma membrane, the viral nucleocapsid and surface glycoproteins.

The replication of Pneumorivuses, from viral factories formation and polymerase activities to assembly of the virions, depends on various regulated protein-protein interactions. Most interestingly, the interactions between viral proteins, which have no counterpart in cells and are highly conserved, as well as the viral enzymatic activities of the L polymerase, are ideal targets for rational drug design. In this context, the BMP team has developed specific topics of research in order to address fundamental questions of Pneumoviruses multiplication, but also to investigate to potential of new antiviral strategies.