What do secreted phospholipases A2 have to offer in combat against different viruses up to SARS-CoV-2?

Abstract

Secreted phospholipases A₂ (sPLA₂s) form a widespread group of structurally-related enzymes that catalyse the hydrolysis of the sn-2 ester bond of glycerophospholipids to produce free fatty acids and lysophospholipids. In humans, nine catalytically active and two inactive sPLA₂ proteins have been identified. These enzymes play diverse biological roles, including host defence against bacteria, parasites and viruses. Several of these endogenous sPLA₂s may play a defensive role in viral infections, as they display in vitro antiviral activity by both direct and indirect mechanisms. However, endogenous sPLA₂s may also exert an offensive and negative role, dampening the antiviral response or promoting inflammation in animal models of viral infection. Similarly, several exogenous sPLA₂s, most of them from snake venoms and other animal venoms, possess in vitro antiviral activities. Thus, both endogenous and exogenous sPLA₂s may be exploited for the development of new antiviral substances or as therapeutic targets for antagonistic drugs that may promote a more robust antiviral response. In this review, the antiviral versus proviral role of both endogenous and exogenous sPLA₂s against various viruses including coronaviruses is presented. Based on the highlighted developments in this area of research, possible directions of future investigation are envisaged. One of them is also a possibility of exploiting sPLA₂s as biological markers of the severity of the Covid-19 pandemic caused by SARS-CoV-2 infection.

Keywords: Antiviral action; Covid-19; Host defence; SARS-CoV-2; Secreted phospholipase A(2); Viruses.

Fig. 1

The antiviral action of endogenous sPLA₂s in in vitro cell systems. Some sPLA₂s, for example human, may act on viruses either directly, by degrading their lipid envelope (virucidal effect?), such as in the case of HIV-1, or indirectly, by acting on cell lipid membranes to prevent effective production of viral particles, such as in the case of non-enveloped adenoviruses. Via enzymatic activity, sPLA₂s hydrolyse phospholipids (PL) from the virus or infected cellular membranes to produce lysophospholipids (LPL) and free fatty acids (FA) that can disturb some key steps of the viral life cycle or lipid metabolism of the host cell. The enveloped virus (e.g. HIV-1), with a lipid membrane derived from host plasma membrane, and the non-enveloped (no lipid) virus (e.g. adenovirus) are shown in violet and blue, respectively. The dashed line separates direct versus indirect sPLA₂ actions on cells. CAR, coxsackievirus and adenovirus receptor.

Fig. 2

The antiviral action of exogenous sPLA₂s in in vitro cell systems. Direct action: certain venom sPLA₂s may exert an antiviral activity by direct hydrolysis of the lipid viral envelope (virucidal effect?). The surface of various enveloped viruses, with the lipid membrane budding from different host cell membranes, is shown by different colours (orange, originating from the endoplasmic reticulum; blue-green, from the Golgi apparatus; green, from the plasma membrane; violet, from the plasma membrane (e.g. HIV-1) or endoplasmic reticulum). Indirect action: venom sPLA₂s may exert antiviral activity by binding and hydrolysis of host cell membranes, thereby inhibiting one or several of the first steps of viral infection: from binding of viruses to entry or virus-driven lipid metabolism. The dashed line separates both direct and indirect sPLA₂ actions on cells. A red curved arrow denotes the unsuccessful attack of a virus on the host cell as a result of the sPLA₂ action. AP-sPLA₂, a catalytically-active sPLA₂ from Acanthaster planci starfish; CB, crotoxin B subunit; CM-II and CM-III, catalytically-active sPLA₂s from Naja mossambica mossambica snake venom; Mt-I, a catalytically-active sPLA₂ from Bothrops asper snake venom. Other abbreviations used are the same as those in Fig. 1 and Table 2.