Scrub typhus is a contagious disease caused by Orientia tsutsugamushi, which was transmitted to humans through the bite of larval trombiculid mites. It poses a significant public health threat and is a major concern for travelers worldwide. In the Asia-Pacific region alone, over one billion people are at risk of Orientia tsutsugamushi infection (Taylor et al., 2015). China, particularly the Guangxi Zhuang Autonomous Region in southern China, was considered a highly endemic area for scrub typhus. The primary clinical manifestations of scrub typhus include fever, rash, eschar, and enlarged lymph nodes. If left untreated, the disease can lead to various complications such as toxic hepatitis, myocarditis, pneumonia, meningoencephalitis, acute renal failure, and disseminated intravascular coagulation. In severe cases, septic shock and multiple organ failure can occur, resulting in a high fatality rate ranging from 30 to 70% (Taylor et al., 2015). Orientia tsutsugamushi primarily targets the systemic vascular endothelial system and parasitizes host endothelial cells, macrophages, monocytes, and dendritic cells (Kang et al., 2017). While Th1-mediated cellular immunity plays a crucial role in the body’s defense against this pathogen, an excessive Th1-type immune response can also cause tissue damage (Anwesha and Smita, 2021; James et al., 2021). Studies have demonstrated that serum levels of inflammatory cytokines such as IL-6, IL-8, IL-10, MCP-1, and TNF are strongly associated with the severity of scrub typhus (Inthawong et al., 2023).

Helicobacter pylori is a gram-negative bacterium that colonizes the mucosal surface of the stomach and establishes a lifelong, chronic infection. In recent years, there has been growing interest in the relationship between H. pylori and extragastric diseases. Research has shown that H. pylori was closely associated with infectious diseases caused by pathogens such as HIV, HCV, and brucella (Furusyo et al., 2011; Afrasiabian et al., 2017; Guo et al., 2021). Additionally, H. pylori may have a protective role against tuberculosis, allergic diseases, asthma, shigellosis, and other diarrheal diseases (Blaser et al., 2008; Perry et al., 2010; Cohen et al., 2012). Upon colonization, H. pylori activates NF-κB transcription factors, leading to the secretion of chemokines like IL-8 by epithelial cells and other cells. This attracts and activates inflammatory cells, promotes the production of Th1-type cytokines such as IFN-γ, and contributes to gastric inflammation (Bridge and Merrell, 2013). The virulence protein CagA, expressed by H. pylori, plays a significant role in H. pylori-host interactions. Individuals who test positive for CagA may experience more severe tissue inflammation and elicit stronger cytokine responses (Bridge and Merrell, 2013). Furthermore, H. pylori induces the secretion of IL-10 through the regulatory T cell (Treg) network, which helps control local inflammation and maintain immune homeostasis. This immune response is particularly pronounced in infections with cagA+/vacA s1m1 strains, and co-infection with H. pylori and helminths can also increase susceptibility to tuberculosis due to dysregulated immune responses (Bustamante-Rengifo et al., 2021). These immune mechanisms contribute to the complex interactions between H. pylori and various infectious diseases.

Infection with Orientia tsutsugamushi in humans can manifest with a wide range of clinical symptoms, varying from mild (asymptomatic) to severe and potentially life-threatening conditions (Park et al., 2021; Devamani et al., 2022). The underlying mechanisms for these variations are not fully understood, but it was believed that factors such as the strain of Orientia tsutsugamushi and the immune status of the host may play a role (Elliott et al., 2019). Therefore, it is important to investigate whether certain infectious factors that influence host immunity have a synergistic effect on the development of scrub typhus. Both H. pylori infection (Fulian et al., 2009) and scrub typhus (Seung-Ji et al., 2016) exhibit a tendency towards Th1 immune responses and share similarities in their immune mechanisms. It was speculated that H. pylori infection may alter the body’s susceptibility to Orientia tsutsugamushi and potentially have a synergistic pathogenic effect. Hence, this study aims to explore the correlation between H. pylori, its various subtypes, and scrub typhus.

Helicobacter pylori infection is commonly acquired during childhood and if left untreated, it can persist for a lifetime (Frenck and Clemens, 2003). In contrast, scrub typhus is an acute infectious disease caused by opportunistic infection of the host with Orientia tsutsugamushi. The status of H. pylori infection in scrub typhus patients and whether H. pylori infection has an impact on the occurrence and development of scrub typhus has not been reported. Epidemiological surveys have shown that the infection rate of H. pylori infection is related to social economic situation, living conditions, sanitary conditions and living habits, occupation and quality of drinking water (Xu Wenting and Chengfu, 2022). The prevalence of scrub typhus is also found in specific populations (e.g., military personnel or plantation workers) and agricultural staff in townships (Devamani et al., 2022). To avoid any influence of environmental and occupational factors on the study results, we strictly matched the regional distribution, age, and gender of the Tsutsugamushi patients and the healthy medical examination population.

This study has made a novel discovery, demonstrating that the prevalence of H. pylori infection was significantly higher in scrub typhus patients compared to healthy subjects (89.7% vs. 53.8%, p < 0.05). This suggests that individuals infected with Orientia tsutsugamushi are more likely to develop typical scrub typhus if they already have an existing H. pylori infection. This finding may help explain why not all Orientia tsutsugamushi infected hosts develop tsutsugamushi (Park et al., 2021). The exact mechanism underlying this phenomenon is not yet fully understood. However, it is believed that dysregulation of cytokine levels, Th1/Th2 cytokine imbalance, and T lymphocyte apoptosis during acute infection with H. tsutsugamushi play a role in pathogenesis, indicating that virulence of Orientia tsutsugamushi alone is not solely responsible, but host immune responses also contribute (Seung-Ji et al., 2016). H. pylori infection triggers activation of NF-xB transcription factors, leading to secretion of IL-8 and other chemokines by epithelial cells or other cells, which stimulate chemotaxis and activation of inflammatory cells, resulting in an inflammatory response (Bridge and Merrell, 2013). Cytokines induced by H. pylori infection act on tissues and organs throughout the body via blood circulation, potentially contributing to the typical clinical manifestations observed in scrub typhus patients with H. pylori infection due to the combined effect of Th1 cytokines.

It is notewothy that the effect of H. pylori infection on host immunity is multifaceted and consequently produces different clinical outcomes when co-infected with other pathogens. During H. pylori infection, neutrophils, B and T lymphocytes infiltrate in the gastric and duodenal mucosa, but they are unsuccessful in clearing the infection. This may be attributed to inadequate cytokine secretion and immune response down-regulation due to an increase in the number of regulatory T cells (Tregs) (Hu et al., 2009). Other studies have also shown an increase in the number of Tregs and a decrease in cytokine production during Helicobacter infection (Ismail et al., 2002; Wang et al., 2004; Park et al., 2007). Increased Tregs activity has been associated with the stability of infections such as leishmaniasis, malaria and tuberculosis, suggesting a possible association between the survival and persistence of some infectious agents and the immunosuppression of Tregs (Belkaid et al., 2002). This also partly explains why H. pylori may have a protective effect on tuberculosis, allergic diseases, asthma, shigellosis and other diarrhea diseases (Blaser et al., 2008; Perry et al., 2010; Cohen et al., 2012). Furthermore, H. pylori replicates and retains cytoplasmic MHC class II molecules within the autophagosome; it also hampers IL-12 production and triggers IL-10 secretion, thus hindering the antimicrobial Th1 response (Gorvel et al., 2014). Therefore, we infer that the robust antimicrobial Th1 response that ought to have been initiated in individuals infected with H. pylori at the onset of Orientia tsutsugamushi invasion might be attenuated; in other words, the host’s anti-infective immune response has been modified during chronic H. pylori infection, augmenting susceptibility to tsutsugamushi.

The vast majority of H. pylori infections in childhood are asymptomatic, but some individuals who are infected may still develop gastrointestinal or extragastrointestinal diseases. In addition to host genetic factors, the possible mechanism for this is closely associated with the virulence type of H. pylori strains, particularly the infection by CagA-positive strains (Bridge and Merrell, 2013). H. pylori possesses a range of virulence factors, including VacA, urease, CagA, heat shock proteins, and neutrophil activating proteins (Fulian et al., 2009). Among these, CagA stands out as one of the most crucial virulence factors. Strains of H. pylori that contain the CagA gene are known as high-virulence strains, as they express both VacA and CagA proteins. On the other hand, H. pylori strains without the CagA gene are classified as low-virulence strains, lacking expression of VacA and CagA proteins. In this study, immunoblotting was employed for the diagnosis of H. pylori infection through strain typing, allowing for an analysis of the correlation between different types of H. pylori infection and scrub typhus. The findings revealed a significantly higher prevalence of H. pylori infection in patients with scrub typhus type I (carrying the CagA gene) compared to healthy subjects (89.7% vs. 53.8%, p < 0.05), while the prevalence of H. pylori infection in type II (not carrying the CagA gene) was similar to that in healthy subjects and did not show any statistically significant difference (p > 0.05). Moreover, the multivariate regression analysis indicated that H. pylori infection of type I was an independent risk factor for scrub typhus. Furthermore, among patients afflicted with scrub typhus and experiencing multiple organ damage, the prevalence of type I H. pylori infection amounted to 50.6%, markedly surpassing the incidence of type II H. pylori infection at 15.4% (x2 = 4.735, p = 0.030). These findings suggests that the development of scrub typhus may be associated with the virulence factor of H. pylori containing the CagA gene. Possible mechanisms for this include: on the one hand, CagA is one of the main virulence proteins expressed by H. pylori, significantly increased mRNA expression of C-X-C chemokines in the gastric mucosa of CagA-positive individuals, and strains of H. pylori that produce VacA and CagA proteins cause more severe tissue inflammation and a more intense cytokine response. Additionally, CagA-positive strains were found to be potent inducers of IL-8 (Hu et al., 2009). Therefore, it is speculated that the Th1 response induced by H. pylori type I strain infection may be more intense. On the other hand, the cross immune reaction hypothesis of molecular simulation suggests that because the highly conserved protein sequences of H. pylori organisms have similar antigenic determinants to human vascular endothelium or glandular epithelium, certain antibodies such as CagA antibodies and HSP antibodies are induced to bind to human cells in vivo leading to cellular damage (Hu et al., 2009). Given that the primary pathological damage observed in scrub typhus is vascular endothelial damage, we speculate that the presence of CagA-producing strains of H. pylori infection may contribute to amplified vascular endothelial damage through a yet unknown pathway. This, in turn, could have a synergistic effect on the body’s inflammatory response. Clinically, this manifests as typical symptoms of scrub typhus, involvement of multiple organs, and potentially a predisposition towards severe disease.

There may be some limitations to this study. In this study, immunoblotting was employed to detect serum H. pylori antibodies and classify H. pylori infection. This method is known for its simplicity and high specificity and sensitivity. However, serological studies are prone to data bias, and we did not adopt two tests to minimize potential errors. Secondly, our data analysis was confined solely to serological examinations, thus neglecting the evaluation of other influential factors that could impact H. pylori infection, such as current infection status, household income, education level, and antibiotic usage.

The prevalence of H. pylori infection was significantly greater in patients with scrub typhus than in the healthy population, and the type I H. pylori strain was an independent risk factor for scrub typhus, Moreover, individuals infected with type I H. pylori are more susceptible to experiencing multiple organ damage associated with scrub typhus, suggesting that H. pylori carrying the CagA gene may promote and exacerbate scrub typhus.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by the ethical review committees of Beihai People’s Hospital and the Affiliated Hospital of Youjiang Medical University for Nationalities. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

QD: Writing – review & editing, Data curation, Methodology, Validation, Writing – original draft. HZ: Data curation, Validation, Writing – original draft, Writing – review & editing, Resources. XP: Data curation, Validation, Writing – original draft, Writing – review & editing, Methodology. JC: Data curation, Validation, Writing – review & editing. BX: Data curation, Writing – review & editing, Formal analysis, Methodology, Visualization. CL: Writing – review & editing, Resources, Validation. LiuL: Resources, Validation, Writing – review & editing. FD: Writing – review & editing, Data curation. MH: Writing – review & editing, Validation. LiL: Writing – review & editing, Resources. FH: Writing – review & editing. XL: Writing – review & editing. YH: Writing – review & editing, Conceptualization, Project administration, Supervision. JL: Supervision, Project administration, Supervision, Writing – review & editing, Funding acquisition.