NADH oxidase, a new player in the field of Streptococcus suis infection

Streptococcus suis is a zoonotic pathogen that causes meningitis and bacteremia in patients consuming raw pork meat/blood or having close contact with infected pigs. Although the first human case was reported in 1968 in Denmark,¹ this pathogen is best known for its ability to infect swine. However, after the outbreak in 2005 in Sichuan province, China,¹ S. suis infections in humans have received increasing attention from researchers and clinicians in many other countries, including Thailand and Vietnam. In Vietnam, S. suis has been reported to be the most common pathogen infecting the central nervous system.² In northern Thailand, a prospective study revealed that the incidence rate of S. suis infection was 6.2 per 100,000 individuals in the general population.³ In contrast, in Europe and North America, cases of S. suis infections are limited to individuals who work closely with pigs, such as butchers and pig breeders.⁴ S. suis infection is not only the major cause of bacterial meningitis and sepsis but also frequently causes hearing loss as a sequela. The route of infection for this pathogen is thought to be entry through damaged or injured skin because pig farmers and butchers have higher infection rates. However, recent studies have suggested that S. suis infection may also occur through consumption of raw pork products.^3,5 Based on these observations, wound and oral infections are both likely to be caused by S. suis infection. Once S. suis enters the blood vessels, it circulates throughout the body and causes sepsis or meningitis. S. suis harbors various virulence factors, including the major virulence factor suilysin.⁶ This cholesterol-dependent cytolysin can bind to the cell membrane and forms pores by oligomeric assembly, exhibiting cytotoxicity and hemolysis in host cells. Several publications have reported that the cytotoxicity of suilysin in immune cells facilitates immune evasion in infected hosts^7-9; however, the clinical manifestations of S. suis infection cannot be completely explained by suilysin alone.

In this issue of Virulence, Zheng et al. report that the NADH oxidase of S. suis may represent another virulence factor responsible for escape of S. suis from detection and targeting by the host immune system.¹⁰ Previously, Spx proteins were found to modulate the expression of virulence-associated genes, acting as global regulators of S. suis.¹¹ Under the control of one of the Spx proteins, SpxA1 was found to protect against oxidative stress tolerance and contributed to virulence. Microarray analysis also revealed that SpxA1 regulated the expression of proteins involved in the oxidative stress response; one candidate protein involved in this response was identified as NADH oxidase, and subsequent analyses successfully demonstrated that this protein exhibited tolerance against oxidative stress and contributed to the development of disease in a mouse model.

NADH oxidase catalyzes the reduction of oxygen to H₂O₂ or H₂O through electron transfer from NADH to balance reactive oxygen species (ROS) and is found in various bacterial species.^12-17 ROS usually encounter pathogens as a detrimental response in infected hosts; therefore, NADH oxidase is thought to be involved in escaping clearance of pathogenic bacteria by immune cells. Particularly in streptococci, several reports have shown that NADH oxidase contributes to the establishment of S. pneumoniae, S. agalactiae, and S. sanguinis infections in animal models; now, another streptococcal species, S. suis, has also been identified. In S. suis, the authors clearly showed that the pathogenicity of NADH oxidase is dependent on its enzymatic activity by using the inactive form of NADH oxidase.

To estimate the involvement of NADH oxidase in bacterial pathogenesis, particularly in streptococci, researchers showed that NADH oxidase was localized in the cell wall of S. pneumoniae and functioned as an adherence factor. Moreover, mice immunized with recombinant NADH oxidase survived a lethal challenge with S. pneumoniae.¹² This observation may be confirmed using similar methods in S. suis infection, and the protective effects of immunization by NADH oxidase may explain the influence of NADH oxidase on the development of S. suis infection. It will be interesting to determine whether the NADH oxidases expressed in S. suis and other streptococci function as adherence factors in host cells. Because successful infection of S. suis is dependent on NADH oxidase activity, elucidation of the relationships between NADH oxidase activity in S. suis and its adherence activity in culture cells will provide insights into the entire process of S. suis infection.

In summary, NADH oxidase of S. suis has been shown to contribute to the pathological manifestations of invasive S. suis infection. Combined with findings regarding the pathogenic factor suilysin, these results provide us with a more comprehensive understanding of infection by S. suis and other pathogenic streptococci.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.