Biology subjects

Yang, X. F.

Publications and source records attributed to Yang, X. F..

4 recordsLinked to original sources

bioRxiv2026

Type I interferon signaling promotes early innate control of Borrelia burgdorferi infection

Borrelia burgdorferi, the causative agent of Lyme disease, elicits a robust type I interferon (IFN-I) response that has been strongly associated with chronic inflammatory manifestations such as Lyme arthritis. Although IFN-I is induced early after infection, its functional contribution during the initial stages of B. burgdorferi infection has remained unclear. Here, we identify a critical protective role for IFN-I signaling in the early control of B. burgdorferi. At 5 days post-infection, mice lacking the IFN-I interferon receptor (IFNAR1) exhibited markedly elevated spirochetal burdens at the site of inoculation, indicating that IFN-I is required to restrict early bacterial expansion. By 10 days post-infection, IFNAR1 deficiency resulted in significantly increased bacterial loads in skin and heart tissues, while joint burdens remained unaffected. Mechanistically, IFN-I signaling enhanced macrophage phagocytosis and intracellular killing of B. burgdorferi both in vitro and in vivo, and promoted pro-inflammatory cytokine production and recruitment of innate immune cells to the site of infection. Conversely, pharmacological activation of IFN-I signaling augmented macrophage antimicrobial function and improved bacterial clearance. Together, these findings establish IFN-I as an essential component of early host defense against B. burgdorferi and reveal a time-dependent role for IFN-I signaling in Lyme disease pathogenesis, with protective functions during early infection that contrast with its pathogenic effects at later stages. AUTHOR SUMMARYLyme disease is caused by the spirochete Borrelia burgdorferi, which is transmitted to humans through the bite of infected ticks. Soon after infection, the spirochete must evade the hosts early immune defenses in the skin to disseminate to other tissues and cause disease. Type I interferons (IFN-I) are best known for their antiviral roles, but they are also strongly induced during Lyme disease. While IFN-I responses have been linked to the development of Lyme Arthritis in later stages of infection, their role during the earliest phase of Lyme disease has remained unclear. In this study, we show that IFN-I interferon signaling plays a critical protective role early after B. burgdorferi infection. Mice lacking the IFN-I interferon receptor were unable to efficiently control bacterial growth at the site of infection and showed increased bacterial dissemination. Mechanistically, IFN-I signaling enhanced the ability of macrophages to engulf and kill B. burgdorferi, promoted inflammatory cytokine production, and supported the recruitment of immune cells to the site of infection. Importantly, short-term activation of IFN-I signaling enhanced bacterial clearance, whereas loss of this pathway impaired early immune control. Together, these findings reveal that IFN-I has time-dependent roles during Lyme disease, protecting the host during early infection while contributing to inflammation at later stages. By defining the time-dependent role of IFN-I signaling in Lyme disease, our study advances understanding of how innate immune responses shape infection outcome and highlights potential strategies for enhancing early host defense.

microbiology↗

bioRxiv2024

Positive feedback regulation between RpoS and BosR in the Lyme disease pathogen

In Borrelia burgdorferi, the Lyme disease pathogen, differential gene expression is primarily controlled by the alternative sigma factor RpoS ({sigma}S). Understanding how RpoS levels are regulated is crucial for elucidating how B. burgdorferi is maintained throughout its enzootic cycle. Our recent studies have shown that a homolog of Fur/PerR repressor/activator, BosR, functions as an RNA-binding protein that controls the rpoS mRNA stability. However, the mechanisms of regulation of BosR, particularly in response to host signals and environmental cues, remain largely unclear. In this study, we revealed a positive feedback loop between RpoS and BosR, where RpoS post-transcriptionally regulates BosR levels. Specifically, mutation or deletion of rpoS significantly reduced BosR levels, while artificial induction of rpoS resulted in a dose-dependent increase in BosR levels. Notably, RpoS does not affect bosR mRNA levels but instead modulates the turnover rate of the BosR protein. Furthermore, we demonstrated that environmental cues do not directly influence bosR expression but instead induce rpoS transcription and RpoS production, thereby enhancing BosR protein levels. This discovery adds a new layer of complexity to the RpoN-RpoS pathway and suggests the need to re-evaluate the factors and signals previously believed to regulate RpoS levels through BosR. IMPORTANCELyme disease is the most prevalent arthropod-borne infection in the United States. The etiological agent, Borreliella (or Borrelia) burgdorferi, is maintained in nature through an enzootic cycle involving a tick vector and a mammalian host. RpoS, the master regulator of differential gene expression, plays a crucial role in tick transmission and mammalian infection of B. burgdorferi. This study reveals a positive feedback loop between RpoS and a Fur/PerR homolog. Elucidating this regulatory network is essential for identifying potential therapeutic targets to disrupt B. burgdorferis enzootic cycle. The findings also have broader implications for understanding the regulation of RpoS and Fur/PerR family in other bacteria.

microbiology↗

bioRxiv2024

Borrelia burgdorferi Secretes c-di-AMP as an Extracellular Pathogen-Associated Molecular Pattern to Elicit Type I Interferon Responses in Mammalian Hosts

Borrelia burgdorferi (B. burgdorferi), an extracellular spirochetal pathogen, elicits a type-I interferon (IFN-I) response that contributes to the pathology of Lyme disease, including the development and severity of Lyme arthritis. However, the specific Pathogen-Associated Molecular Patterns (PAMPs) of B. burgdorferi responsible for triggering the IFN-I response are not well understood. Previous studies have identified an unknown, nuclease-resistant component in B. burgdorferi culture supernatants that significantly stimulates the IFN-I response, but its identity remains unknown. In this study, we reveal that B. burgdorferi secretes cyclic-di-adenosine monophosphate (c-di-AMP) as a key extracellular PAMP, inducing the host IFN-I response in macrophages. Using genetically manipulated B. burgdorferi strains, we demonstrate a requirement of c-di-AMP for stimulating IFN-I response by macrophages ex vivo. Additionally, infecting mice with B. burgdorferi alongside exogenous c-di-AMP resulted in a markedly increased IFN-I response in mouse tissues. Furthermore, inactivation or inhibition of the host STING signaling pathway significantly reduced the IFN-I response, indicating that c-di-AMP-induced IFN-I production is STING-dependent. Our findings identify c-di-AMP as a crucial PAMP secreted by B. burgdorferi to elicit the host IFN-I response via activation of STING signaling pathway, suggesting that targeting c-di-AMP production could represent a novel therapeutic strategy against Lyme arthritis. SUMMARYBorrelia burgdorferi, the bacteria that causes Lyme disease, induces a robust host immune response, including the production of type-I interferon (IFN-I). While this response helps combat the infection, it also contributes to complications such as Lyme arthritis. Our research aimed to identify the specific bacterial component that triggers the IFN-I response. We discovered that Borrelia burgdorferi releases a second messenger molecule, cyclic-di-adenosine monophosphate (c-di-AMP), which is recognized by host immune cells and subsequently triggers IFN-I production. This finding is significant as it advances our understanding of Lyme disease pathogenesis and offers a new strategy to tackle Lyme disease by targeting the production of c-di-AMP, in which we may be able to reduce the severity of the disease and mitigate long-term tissue damage. One sentence summaryBorrelia burgdorferi c-di-AMP induces Type I IFN response

immunology↗

bioRxiv2024

MCP5, a methyl-accepting chemotaxis protein regulated by both the Hk1-Rrp1 and Rrp2-RpoN-RpoS pathways, is required for the immune evasion of Borrelia burgdorferi

Borrelia (or Borreliella) burgdorferi, the causative agent of Lyme disease, is a motile and invasive zoonotic pathogen, adept at navigating between its arthropod vector and mammalian host. While motility and chemotaxis are well established as essential for its enzootic cycle, the function of methyl-accepting chemotaxis proteins (MCPs) in the infectious cycle of B. burgdorferi remains unclear. In this study, we demonstrate that MCP5, one of the most abundant MCPs in B. burgdorferi, is differentially expressed in response to environmental signals as well as at different stages of the pathogens enzootic cycle. Specifically, the expression of mcp5 is regulated by the Hk1-Rrp1 and Rrp2-RpoN-RpoS pathways, which are critical for the spirochetes colonization of the tick vector and mammalian host, respectively. Infection experiments with an mcp5 mutant revealed that spirochetes lacking MCP5 could not establish infections in either C3H/HeN mice or Severe Combined Immunodeficiency (SCID) mice, which are defective in adaptive immunity, indicating the essential role of MCP5 in mammalian infection. However, the mcp5 mutant could establish infection and disseminate in NOD SCID Gamma (NSG) mice, which are deficient in both adaptive and most innate immune responses, suggesting a crucial role of MCP5 in evading host innate immunity. In the tick vector, the mcp5 mutants survived feeding but failed to transmit to mice, highlighting the importance of MCP5 in transmission. Our findings reveal that MCP5, regulated by the Rrp1 and Rrp2 pathways, is critical for the establishment of infection in mammalian hosts by evading host innate immunity and is important for the transmission of spirochetes from ticks to mammalian hosts, underscoring its potential as a target for intervention strategies. SUMMARYLyme disease is the most commonly reported arthropod-borne illness in the US, Europe, and Asia. The causative agent of Lyme disease, Borrelia burgdorferi, is maintained in an enzootic cycle involving arthropod vectors (Ixodes ticks) and rodent mammalian hosts. Understanding how B. burgdorferi moves within this natural cycle is crucial for developing new strategies to combat Lyme disease. The complex nature of the enzootic cycle necessitates sensory-guided movement in response to environmental stimuli. B. burgdorferi possesses a unique and intricate chemotaxis signaling system, with methyl-accepting chemotaxis proteins (MCPs) at its core. These proteins are responsible for sensing environmental signals and guiding bacterial movement toward or away from stimuli. This study found that one of the MCPs, MCP5, is highly expressed and differentially regulated during the enzootic cycle by the Hk1-Rrp1 and Rrp2-RpoN-RpoS pathways. MCP5 is crucial for mammalian infection, aiding in immune evasion and transmission from ticks to mammals, providing a foundation for further research into B. burgdorferis navigation within its hosts.

microbiology↗