A tick saliva serpin, IxsS17 inhibits host innate immune system proteases and enhances host colonization by Lyme disease agent.

Lyme disease (LD) caused by Borrelia burgdorferi is among the most important human vector borne diseases for which there is no effective prevention method. Identification of tick saliva transmission factors of the LD agent is needed before the highly advocated tick antigen-based vaccine could be developed. We previously reported the highly conserved Ixodes scapularis (Ixs) tick saliva serpin (S) 17 (IxsS17) was highly secreted by B. burgdorferi infected nymphs. Here, we show that IxsS17 promote tick feeding and enhances B. burgdorferi colonization of the host. We show that IxsS17 is not part of a redundant system, and its functional domain reactive center loop (RCL) is 100% conserved in all tick species. Yeast expressed recombinant (r) IxsS17 inhibits effector proteases of inflammation, blood clotting, and complement innate immune systems. Interestingly, differential precipitation analysis revealed novel functional insights that IxsS17 interacts with both effector proteases and regulatory protease inhibitors. For instance, rIxsS17 interacted with blood clotting proteases, fXII, fX, fXII, plasmin, and plasma kallikrein alongside blood clotting regulatory serpins (antithrombin III and heparin cofactor II). Similarly, rIxsS17 interacted with both complement system serine proteases, C1s, C2, and factor I and the regulatory serpin, plasma protease C1 inhibitor. Consistently, we validated that rIxsS17 dose dependently blocked deposition of the complement membrane attack complex via the lectin complement pathway and protected complement sensitive B. burgdorferi from complement-mediated killing. Likewise, co-inoculating C3H/HeN mice with rIxsS17 and B. burgdorferi significantly enhanced colonization of mouse heart and skin organs in a reverse dose dependent manner. Taken together, our data suggests an important role for IxsS17 in tick feeding and B. burgdorferi colonization of the host.

Recent Advancements in Antimycobacterial and Antifungal Drugs: A Patent Perspective.

BACKGROUND: Infections caused by Mycobacterium and pathogenic fungi have risen drastically over the past few decades. Moreover, with the increase in the number of immunocompromised (burn, organ transplant, chemotherapy, HIV) patients, these bacterial and fungal infections have led to alarming mortality rates. The drugs currently in use have become relatively ineffective due to ever increasing phenomenon of multidrug resistance. Furthermore, these drugs suffer with severe toxicity effects and also lack cost effectiveness. OBJECTIVE: Under such compelling circumstances, it is pertinent to find novel and safer drugs with improved properties. One strategy that could be adopted is to identify natural bioactive compounds having antimicrobial potential with minimal side effects. Alternatively, drugs synthesized with the help of combinatorial chemistry leading to enhanced antimicrobial properties could be another strategy. RESULT: This article summarizes at a common platform the current scenario of the available natural as well as synthetic drugs targeting cell envelope that have patentable therapeutic interventions against predominant human bacterial and fungal pathogens.