Almost everyone could potentially contract a common virus that is highly contagious and can be transmitted through various body fluids such as semen, saliva, urine, breast milk, and blood. This means that the people around are highly susceptible to infection. However, for individuals with a normal immune system, this virus usually does not cause significant harm. What we are discussing here is the human cytomegalovirus (HHV-5), which may already exist in many people’s bodies. Nonetheless, we now shift our focus to a member of the Flaviviridae family, the Japanese encephalitis virus (JEV), which has been affecting people in East Asia, Southeast Asia, and the Western Pacific since it was first identified in Japan in 1871.
The initial symptoms of JEV infection may include fever, headache, and general malaise, lasting for 1 to 6 days. In some cases, infected individuals may exhibit more severe reactions, such as acute encephalitis, with symptoms including a stiff neck, coma, hemiplegia, and convulsions. Under these circumstances, the mortality rate for patients can reach up to 30%, and currently, there are no precise medicines for treatment. Among the survivors, up to 40% suffer from permanent neurological damage such as mental impairment, deafness, or epilepsy.
Flaviviruses employ a cunning survival strategy, learning a trick called “viral apoptotic mimicry.” Within our bodies, cells produce phosphatidylserine (PS) and display it on the cell surface as a signal of impending death, to be recognized and promptly cleared by the immune system. By displaying PS on their surface, flaviviruses mimic dying cells, infiltrating immune cells and successfully invading them. They not only proliferate within the host but also find ways to spread among the population. The virus’s surface PS can be converted into another phospholipid, PE, by PS decarboxylase, reducing the number of flavivirus-infected cells, thereby potentially evading further detection by the immune system. It is noteworthy that although vaccines have controlled the spread of JEV, there are still tens of thousands of cases of infection each year worldwide, with about 17,000 deaths resulting from it.
It is well known that the Egyptian mosquito and the Asian tiger mosquito are notorious bloodsuckers and vectors, posing a threat to a wide range of populations by spreading flaviviruses. Nevertheless, compared to the HHV-5 virus, the ability of these viruses to be transmitted through body fluids is greatly lacking. The reason behind this is mainly that our body fluids play a protective role.
In the latest scientific research, an article published in the journal Nature Microbiology has revealed some striking discoveries. Under the leadership of Professor Janis A. Müller from the University Medical Center Ulm in Germany, a team found that while certain viruses such as hepatitis B, human immunodeficiency virus (HIV-1), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can exist in human body fluids like saliva, breast milk, or semen, they rarely transmit through kissing or sexual intercourse.
What particularly needs attention is the Ebola virus (EBOV), which is notorious for causing severe harm to those infected. Furthermore, it can spread through various bodily fluids, such as blood, saliva, tears, sweat, urine, and even vomit and feces. These fluids are highly contagious, and a slight mishap can lead to infection.
Müller’s young research team focuses on exploring how innate immune mechanisms are utilized in the human body to combat flavivirus. In their research, they elucidated methods by which human bodily fluids inhibit the flavivirus, providing a deeper understanding of the diverse transmission of viruses.
In their research, they discovered that PS-liposomes (liposomes with phosphatidylserine PS on their surface) can compete with the Zika virus, likened to a ticket-grabbing scenario. As more people pour in, those originally grabbing tickets will struggle to secure enough. Similarly, by competing with the Zika virus for PS receptors on immune cells, PS-liposomes effectively inhibit virus invasion.
By creating and testing these liposomes, and using PC-liposomes (phosphatidylcholine) as a control group, researchers confirmed that PS-liposomes could significantly inhibit viral infections, and that this inhibitory effect is dose-dependent.
The study shows that when there are more than 25 moles percent of PS-liposomes in 1 milliliter of liquid, and the concentration of liposomes is about 2×109 particles, it can effectively inhibit 50% of the virus invasion. Based on this discovery, scientists further explored whether there are similar liposomes in human bodily fluids that can interfere with virus infections.
They collected endogenous vesicles (EV) from human semen, saliva, urine, breast milk, and blood. The study found that, apart from blood, phosphatidylserine (PS) is the highest content lipid class in vesicles from other bodily fluids. The PS content in vesicles from semen and urine is 57.5 mole percent and 56.3 mole percent, respectively; in saliva and breast milk, it is 31.3 mole percent and 17.3 mole percent. However, the content of PS in blood is only 0.1 mole percent.
The semen is particularly rich in PS, two specific PS lipid molecules account for 20% proportion in vesicles from semen and urine. Additionally, there are other types of lipid substances, such as phosphatidylcholine (PC) in blood vesicles, which is as high as 17.7 mole percent; sphingomyelin (SM) in breast milk is 24.6 mole percent, and the phosphatidylethanolamine (PE) in breast milk is 18.8 mole percent. PE phospholipids can synergistically enhance the binding of PS and the PS receptors on immune cells, a phenomenon that is particularly significant in saliva and urine. In contrast, the levels of PS and PE in blood are low, while the PC content is about three times higher than in saliva and semen.
Further research has revealed that these PS-containing vesicles in body fluids show effective inhibition of dengue fever virus and West Nile virus alike. Moreover, these vesicles can also defend against other virus family pathogens such as Chikungunya virus (CHIKV), Ebola virus, and Vesicular stomatitis virus (VSV). This suggests that these PS-rich vesicles in body fluids can provide a broad spectrum of antiviral capability to our innate immune defense by inhibiting viral infection. This might also explain why flaviviruses like dengue fever are primarily transmitted through blood and blood-sucking arthropods, rather than direct contact between humans.
For viruses that depend on other receptors to infect cells, such as SARS-CoV-2, HIV-1, Herpes Simplex Virus (HSV), Human Cytomegalovirus (HCMV), these PS-containing vesicles seem to have no inhibitory effect. Even in the Flavivirus family, Hepatitis C Virus (HCV) is an exception; it also uses other receptors during infection, therefore these vesicles are not effective in defending against HCV.
