Biology subjects

Angara, R. K.

Publications and source records attributed to Angara, R. K..

3 recordsLinked to original sources

bioRxiv2023

The novel bacterial effector protein CbEPF1 mediates ER-LD membrane contacts to regulate host lipid droplet metabolism

Effective intracellular communication between cellular organelles is pivotal for maintaining cellular homeostasis. Tether proteins, which are responsible for establishing membrane contact sites between cell organelles, enable direct communication between organelles and ultimately influence organelle function and host cell homeostasis. While recent research has identified tether proteins in several bacterial pathogens, their functions have predominantly been associated with mediating inter-organelle communication specifically between the bacteria containing vacuole (BCV) and the host endoplasmic reticulum (ER). However, this study reveals a novel bacterial effector protein, CbEPF1, which acts as a molecular tether beyond the confines of the BCV and facilitates interactions between host cell organelles. Coxiella burnetii, an obligate intracellular bacterial pathogen, encodes the FFAT motif-containing protein CbEPF1 which localizes to host lipid droplets (LDs). CbEPF1 establishes inter-organelle contact sites between host LDs and the ER through its interactions with VAP family proteins. Intriguingly, CbEPF1 modulates growth of host LDs in a FFAT motif-dependent manner. These findings highlight the potential for bacterial effector proteins to impact host cellular homeostasis by manipulating inter-organelle communication beyond conventional BCVs.

cell biology↗

bioRxiv2023

Host autophagy is exploited by the intracellular parasite Toxoplasma gondii to enhance amino acids levels.

Toxoplasma gondii, a widespread parasite, has the ability to infect nearly any nucleated cell in warm-blooded vertebrates. It is estimated that around 2 billion people globally have been infected by this pathogen. Although most healthy individuals can effectively control parasite replication, certain parasites may evade the immune response, establishing cysts in the brain that are refractory to the immune system and resistance to available drugs. For its chronic persistence in the brain, the parasite relies on host cells nutrients, particularly amino acids and lipids. Therefore, understanding how latent parasites persist in the brain is crucial for identifying potential drug targets against chronic forms. While shielded within parasitophorous vacuoles (PVs) or cysts, Toxoplasma exploits the host endoplasmic reticulum (ER) metabolism to sustains its persistence in the brain, resulting in host neurological alterations. In this study, we demonstrate that T. gondii disrupts the host ER homeostasis, resulting in accumulation of unfolded protein with the host ER. The host counters this stress by initiating an autophagic pathway known as ER-phagy, which breaks down unfolded proteins into amino acids, promoting their recycling. Remarkably, the persistence of latent forms in cell culture as well as behavioral changes in mice caused by the latent infection could be successfully reversed by restricting the availability of various amino acids during T. gondi infection. Our findings unveil the underlying mechanisms employed by T. gondii to exploit host ER and lysosomal pathways, enhancing nutrient levels during infection. These insights provide new strategies for the treatment of toxoplasmosis. ImportanceIntracellular parasites employ several mechanisms to manipulate the cellular environment, enabling them to persist in the host. Toxoplasma gondii, a single-celled parasite, possesses the ability to infect virtually any nucleated cell of warm-blooded vertebrates, including nearly 2 billion people worldwide. Unfortunately, existing treatments and immune responses are not entirely effective in eliminating the chronic persisting forms of the parasite. This study reveals that T. gondii induces the hosts autophagic pathway to boost amino acid levels in infected cells. The depletion of amino acids, in turn, influences the persistence of the parasites chronic forms, resulting in a reduction of neurological alterations caused by chronic infection in mice. Significantly, our investigation establishes the crucial role of host ER-phagy in the parasites persistence within the host during latent infection.

microbiology↗

bioRxiv2023

Coxiella burnetii actively blocks IL-17-induced oxidative stress in macrophages

Coxiella burnetii is a highly infectious, aerosol-transmitted obligate intracellular bacterium that causes human Q fever and replicates within alveolar macrophages during pulmonary infection. Successful infection requires the C. burnetii Type IVB secretion system (T4BSS), which delivers bacterial effector proteins into the host cytoplasm to remodel host processes and suppress the innate immune response. In the lung, IL-17 promotes antibacterial immunity by activating ACT1-TRAF6-dependent pathways that drive inflammatory gene expression, reactive oxygen species production, and neutrophil recruitment. However, how intracellular pathogens subvert IL-17 signaling pathways to promote survival within macrophages remains poorly understood. Here, we show that C. burnetii evades IL-17-mediated host defense by targeting TRAF6, a central ubiquitin-dependent regulator of innate immune signaling. IL-17 signaling through ACT1-TRAF6 restricts C. burnetii viability in macrophages; however, C. burnetii impairs IL-17-induced NF-{kappa}B and MAPK activation, particularly JNK phosphorylation. C. burnetii T4BSS activity suppresses IL-17-driven reactive oxygen species production and neutrophil recruitment. We identify the C. burnetii T4BSS effector EmcB as a TRAF6-targeting deubiquitinase that disrupts IL-17-dependent antimicrobial and chemotactic responses. Together these findings reveal that C. burnetii downregulates intracellular innate immune signaling by targeting TRAF6, enabling evasion of the macrophage antimicrobial response and limiting neutrophil-mediated immunity. Significance StatementCoxiella burnetii causes Q fever and survives inside macrophages, immune cells that normally help eliminate inhaled pathogens. This study identifies a mechanism by which C. burnetii weakens macrophage defenses. We show that the bacterium disrupts macrophage IL-17 signaling, an immune pathway that promotes inflammatory gene expression, reactive oxygen species production, and neutrophil recruitment. Mechanistically, C. burnetii uses the secreted enzyme EmcB to target TRAF6, a central signaling protein required for IL-17-dependent antimicrobial responses. These findings reveal how an intracellular bacterial pathogen disables a key immune signaling hub to promote survival and limit innate immune activation, providing broader insight into how pathogens manipulate host immunity.

microbiology↗