Paridiprubart inhibits TLR4-dependant NF-κB activation by multiple pathogens (preprint)

Respiratory pathogens such as SARS-CoV-2 and influenza can activate an exaggerated inflammatory response (cytokine storm) in the lungs that may result in acute respiratory distress syndrome (ARDS), hospitalization, and death. Therapies that target a specific pathogen (i.e. anti-virals) must, by nature, be selected after a specific diagnosis and may become ineffective due to pathogen evolution. An alternate strategy is to counter the exaggerated innate immune response present in ARDS patients using host-directed drug therapies that are agnostic to the infectious agent to overcome both of these challenges. Originally described as the innate immune receptor for lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4) is now understood to be an important mediator of inflammation caused by a variety of pathogen-associated molecular patterns (PAMPs) and host-derived damage-associated molecular patterns (DAMPs). Here we show that paridiprubart, a monoclonal antibody that prevents TLR4 dimer formation, inhibits the response to TLR4 agonists including LPS, the SARS-CoV-2 spike protein, the DAMP high mobility group box 1 (HMGB1), as well as the NF-{kappa}B response to infection by both viral and bacterial pathogens. Notable in this regard, we demonstrate that SARS-CoV-2 increases HMGB1 levels, and that paridiprubart inhibits both the SARS-CoV-2 and HMGB1-triggered NF-{kappa}B response, illustrating its potential to suppress this self-amplifying inflammatory signal. We also observed that the inhibitory effect of paridiprubart is apparent when cells are exposed to the SARS-CoV-2 spike protein, which is itself a direct TLR4 agonist. In the context of active infection, paridiprubart suppressed the NF-{kappa}B-dependent response elicited by infection with SARS-CoV-2, the seasonal coronavirus 229E, influenza A virus or Haemophilus influenzae, a gram-negative bacterial pathogen. Combined, these findings reinforce the central role played by TLR4 in the inflammatory response to infection by diverse pathogens, and demonstrates the protective potential of paridiprubart-dependent inhibition of pathogenic TLR4 responses.

Genomic surveillance of SARS-CoV-2 reveals community transmission of a major lineage during the early pandemic phase in Brazil (preprint)

Despite all efforts to control the COVID-19 spread, the SARS-CoV-2 reached South America within three months after its first detection in China, and Brazil became one of the hotspots of COVID-19 in the world. Several SARS-CoV-2 lineages have been identified and some local clusters have been described in this early pandemic phase in Western countries. Here we investigated the genetic diversity of SARS-CoV-2 during the early phase (late February to late April) of the epidemic in Brazil. Phylogenetic analyses revealed multiple introductions of SARS-CoV-2 in Brazil and the community transmission of a major B.1.1 lineage defined by two amino acid substitutions in the Nucleocapsid and ORF6. This SARS-CoV-2 Brazilian lineage was probably established during February 2020 and rapidly spread through the country, reaching different Brazilian regions by the middle of March 2020. Our study also supports occasional exportations of this Brazilian B.1.1 lineage to neighboring South American countries and to more distant countries before the implementation of international air travels restrictions in Brazil.