Thread by @ZdenekVrozina

Why do men with severe COVID-19 often show low testosterone and cholesterol? For years, we knew ACE2 was abundant in testicular tissue.
Now we have direct evidence - SARS-CoV-2 hijacks Leydig cells, diverting cholesterol away from hormones and into viral particles.🧵

For the first time, SARS-CoV-2 particles were found inside lipid inclusions and organelles of Leydig cells - the testicular cells that produce testosterone.
This discovery helps explain why men with severe COVID-19 often show low testosterone and cholesterol.

Already since 2020, studies had pointed out that ACE2 is highly expressed in testicular tissue, especially in Leydig and Sertoli cells.
Histopathological studies in deceased patients showed testicular damage - inflammation, degeneration, reduced spermatogenesis.

In a transgenic mouse model (K18-hACE2), the virus directly infected Leydig cells.
These cells store cholesterol and contain the machinery for steroid hormone production - making them an ideal viral target.

SARS-CoV-2 enters Leydig cells via the ACE2 receptor, highly expressed in both mouse and human testes.
Once inside, the virus hijacks the metabolic machinery for its own replication.

The virus rewires lipid metabolism.
Cholesterol, normally used for testosterone, is redirected to build viral particles.
Infected cells become full of lipids, yet testosterone production drops sharply.
Seen in mice, but consistent with clinical findings in humans.

Even worse - infected Leydig cells switch roles.
Instead of producing steroid hormones, they adopt an immune-like profile and begin releasing pro-inflammatory cytokines - further suppressing testosterone.

Clinically, patients with severe COVID-19 show
lower cholesterol (total, LDL, HDL),
reduced testosterone in men.
The mouse data provide the mechanism. The human data confirm the pattern.

Mechanism demonstrated in mice with the ancestral SARS-CoV-2 strain.
Human data across multiple variants confirm the hormonal & metabolic consequences.

This isn’t the first virus to exploit the testis or lipids.
Zika infects Sertoli cells, impairing fertility.
Mumps can cause orchitis and testicular damage.
SARS-CoV-2 now joins this list with direct effects on Leydig cells.

Viruses also hijack lipid metabolism elsewhere.
HCV uses lipid droplets in the liver to build new particles.
HIV alters cholesterol metabolism in immune cells.
SARS-CoV-2 does the same in the testis - repurposing cholesterol away from hormones and into viral replication.

Oliveira at al., SARS-CoV-2 exploits steroidogenic machinery, triggers lipid metabolism for viral replication and induces immune response in Leydig cells of K18-hACE2 mice. frontiersin.org/journals/cellu…