Small Rho GTPases and Cholesterol Biosynthetic Pathway Intermediates in African Swine Fever Virus Infection

Abstract

The integrity of the cholesterol biosynthesis pathway is required for efficient African swine fever virus (ASFV) infection. Incorporation of prenyl groups into Rho GTPases plays a key role in several stages of ASFV infection, since both geranylgeranyl and farnesyl pyrophosphates are required at different infection steps. We found that Rho GTPase inhibition impaired virus morphogenesis and resulted in an abnormal viral factory size with the accumulation of envelope precursors and immature virions. Furthermore, abundant defective virions reached the plasma membrane, and filopodia formation in exocytosis was abrogated. Rac1 was activated at early ASFV infection stages, coincident with microtubule acetylation, a process that stabilizes microtubules for virus transport. Rac1 inhibition did not affect the viral entry step itself but impaired subsequent virus production. We found that specific Rac1 inhibition impaired viral induced microtubule acetylation and viral intracellular transport. These findings highlight that viral infection is the result of a carefully orchestrated modulation of Rho family GTPase activity within the host cell; this modulation results critical for virus morphogenesis and in turn, triggers cytoskeleton remodeling, such as microtubule stabilization for viral transport during early infection.

Host cell targets for African swine fever virus

“…In fact, 166 the integrity of the entire cholesterol biosynthesis pathway was found to be critical at 167 several post infection times (Quetglas et al, 2012). However, some differences were 168 found in macrophages and in Vero cells in the presence of nystatin, a drug that 169 disorganizes cholesterol in lipid rafts without reducing cholesterol levels (Hernaez and 170 Alonso, 2010).…”

“…ATF6 is necessary for ASFV replication; however, the virus prevents the transcriptional 432 induction of some ATF6-target genes, such as X-box binding Protein-1 (XBP1) and BiP, 433 but not calnexin or calreticulin (Galindo et al, 2012). 434…”

“…337Microtubules play a role in virus transport to the perinuclear area and incoming virus 338 particles are found associated to stabilized microtubules(Quetglas et al, 2012). Also,Alonso et al, 2001; Carvalho et al, 1988;de Matos and Carvalho, 1993; Heath et al, 343 2001).…”

Rho’ing in and out of cells

“…100,101 Likewise, in African Swine Fever Virus (ASFV) infection, Rac1-mediated microtubule acetylation is required for microtubule stabilization during viral transport. 102 Hence, several viruses make use of RhoA and/or Rac1 GTPase signaling to modulate microtubules for establishment of infection or nuclear delivery of the viral genome.…”

Lipid Involvement in Viral Infections: Present and Future Perspectives for the Design of Antiviral Strategies

“…Examples of host cell genes associated to lipid metabolism and involved in viral replication associated to the infection of animal pathogens like African swine fever virus [115]. On the other hand, sterols have been involved in the replication of plant pathogens, for example tomato bushy stunt virus (TBSV) [104].…”