Suppression of annexin A1 and its receptor reduces herpes simplex virus 1 lethality in mice

Abstract

Herpes simplex virus 1 (HSV-1)-induced encephalitis is the most common cause of sporadic, fatal encephalitis in humans. HSV-1 has at least 10 different envelope glycoproteins, which can promote virus infection. The ligands for most of the envelope glycoproteins and the significance of these ligands in virus-induced encephalitis remain elusive. Here, we show that glycoprotein E (gE) binds to the cellular protein, annexin A1 (Anx-A1) to enhance infection. Anx-A1 can be detected on the surface of cells permissive for HSV-1 before infection and on virions. Suppression of Anx-A1 or its receptor, formyl peptide receptor 2 (FPR2), on the cell surface and gE or Anx-A1 on HSV-1 envelopes reduced virus binding to cells. Importantly, Anx-A1 knockout, Anx-A1 knockdown, or treatments with the FPR2 antagonist reduced the mortality and tissue viral loads of infected mice. Our results show that Anx-A1 is a novel enhancing factor of HSV-1 infection. Anx-A1-deficient mice displayed no evident physiology and behavior changes. Hence, targeting Anx-A1 and FPR2 could be a promising prophylaxis or adjuvant therapy to decrease HSV-1 lethality.

Resolution pharmacology and the treatment of infectious diseases

“…Furthermore, herpes virus and IAV exploit the AnxA1 pathway by utilizing the FPR2 receptor to enhance virus uptake by host cells. Both the glycoprotein E (gE) of herpes virus and the envelope protein of IAV bind to AnxA1 and utilize FPR2 for cell entry (Arora et al, 2016; Tcherniuk et al, 2016; Wang et al, 2022).…”

The Multifaceted Role of Annexin A1 in Viral Infections

“…The Herpes simplex virus 1 (HSV-1) is a neurotropic virus that causes latent infection in humans and can cause clinical symptoms ranging from painful sores to life-threatening neuroinflammation [ 135 ]. AnxA1 is expressed on the surface of cells that are known to be permissive for HSV-1 replication, including A549 and N18 cells (derived from mouse neuroblastoma) [ 20 ]. It was reported that the binding of AnxA1 to glycoprotein E (gE) on the HSV-1 envelope enhances virus binding and facilitates the infection of A549 or N18 cells.…”

“…It was reported that the binding of AnxA1 to glycoprotein E (gE) on the HSV-1 envelope enhances virus binding and facilitates the infection of A549 or N18 cells. In addition, the FPR2 receptor antagonist, WRW4, was shown to reduce HSV-1 binding to the cell surface [ 20 ]. Furthermore, in HSV1 encephalitis in mice, the absence of AnxA1 or FPR2 was associated with reduced mortality and lower tissue viral loads compared to infected WT controls [ 20 ].…”

“…In addition, the FPR2 receptor antagonist, WRW4, was shown to reduce HSV-1 binding to the cell surface [ 20 ]. Furthermore, in HSV1 encephalitis in mice, the absence of AnxA1 or FPR2 was associated with reduced mortality and lower tissue viral loads compared to infected WT controls [ 20 ]. These findings suggest that the antagonism of the AnxA1/FPR2 axis could be a potential target for reducing the lethality of encephalitis caused by HSV-1.…”

“…In this regard, one would assume that AnxA1 is mainly protective in the context of viral diseases. However, recent studies have shown that the role of this molecule during viral infections is more complex than previously thought and it can be beneficial or detrimental depending on the pathogen and timing of production/administration [ 18 , 19 , 20 , 21 ].…”