editorial The Future of Utilizing in Vivo Interbacterial Interactions to Develop Novel Anti-Bacteria Therapeutics and Vaccines
Yang Fu*
Department of Microbiology and Immunobiology, Harvard Medical School
*Corresponding author: Yang Fu, Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA, 02115, USA. Tel: +1617 834-3608; E-Mail: yang_fu@hms.harvard.ed
Received Date: 30 January, 2017; Accepted Date: 30 January, 2017; Published Date: 6 February, 2017
Citation: Yang Fu (2017) The Future of utilizing in Vivo Interbacterial Interactions to Develop Novel Anti-Bacteria Therapeutics and Vaccines. J Vaccines Immunol 2017: 105. DOI: 10.29011/2575-789X.000105
Enteric infectious disease caused by bacteria pathogens is one of the major global public health issues for centuries. Through the long term effort of the generations of genius scientists, to date, we have already developed many effective vaccines and successful antibiotics to cope with the threat. On the other hand, pathogenic strains involved to counter the traditional drugs and achieve immune escape, side-effects caused by broad-spectrum antibiotics, emerging diseases and so on, remaining request the development of novel anti-bacteria therapeutics. Nowadays, with the high throughput NGS screening combined with the new powerful animal models, applications of bacteria type VI secretion systems and the recently boomed research of human gut microbiome, investigators have more and more pay attention to the potential to utilize both the intra and inter species bacterial interactionsin vivo. Here, we attempt to make a mini review the recently findings in the field and give a perspective for the new approach to develop antimicrobial agents.
Emerging High Specificity Anti-Bacteria Systems
Remarkably, bacteria have a plethora of immunity strategies that protect them not only against the host but also against attacks by unwanted genetic elements or aggressive bacteria cells. These range from relatively nonspecific restriction-modification systems, to adaptable and target directed CRISPR systems [10], to highly specific toxin-antitoxin immunity systems [11]. In the latter case, immunity to toxic diffusible proteins such as bacteriocins, or toxic molecules associated with cell-cell contact dependent inhibitory systems (e.g., the CDI system of E. coli) is dependent on the ability of bacterial cell to produce proteins that bind to and inactivate single toxic or inhibitory effectors with a high degree of specificity. Recently, immunity proteins associated with type VI secretion systems (T6SS)have been recognized as critical players in protecting sister cells from the toxic effects of this anti-cellular system [11,12]. The bacterial T6SS corresponds to a dynamic, intracellular contractile organelle [13], that can translocate toxic effectors into both prokaryotic as well as eukaryotic cells [14,15]. Immunity proteins to such toxic effectors protect sister cells from random or induced attacks, the latter being driven by elaborate regulatory systems in some predatory species that detect aggressive T6SS activity in nearby prey cells [16].
A lesson from Vibrio cholerae, the causative agent of the severe diarrheal disease cholera recently has raised up the potential to use T6S as a novel anti-microbiome therapeutic in vivo [17]. Investigators have used transposon mutagenesis sequencing analysis (Tn-Seq) and competition assays to study V.cholerae El Tor C6706 strain intestinal colonization in the modified infant rabbit model [17,18]. Besides the well-known colonization factors overlapped with the ones previously reported in the suckling mice model and human patients, we found that V.cholerae also utilized different mechanisms to gain growth advantages in the host. A strong piece of evidence that V. cholera cell-cell competition occur in vivo is provided by phenotypes related to the T6S.Included in the severe colonization defect group were mutants carrying insertions in tsiV3 and tsiV1, which encode immunity proteins for self-protection to neutralize the cognate bacteriocidal effector proteins VgrG3 and TseL of T6SS, respectively. Further experiments showed that the reduced in vivo fitness of tsiV3 and tsiV1 mutants depends on their co-colonization with strains that have an intact T6SS locus and cognate T6SS effector genes. These results suggest that the T6SSof V. cholerae strain C6706 is functionally expressed in vivo and that antagonistic sister cell-sister cell interactions occur during the infection process. Later on, inter species bacterial competition was also found in planta bacterium pathogens [19] and human commensal bacteroidetes [20, 21]. Besides, intra species bacteria T6S interactions were also found in vivo during salmonella typhi infection [22], and through the development of probiotic commensal strains either sensitive or resistant to the V. cholerae T6SS (Zhao, Fu and Robins, Mekalanos group, unpublished results). All these clues revealed several novel anti-microbiome strategies such like the small molecules that inhibit T6S immunity proteins could be used for highly species-specific anti-infective drugs against Gram- pathogens and pre- or post-inoculated T6S+ probiotic strains that can specific targeting sensitive bacterium.
Speculation Of Utilize the invivo Cell-Cell Contact Microenvironment
Because the T6S is thought to deliver toxic effectors to neighboring cells only through direct cell-cell contact, directly or indirectly measure the extent of cell-cell contact in the animal model may offer more potential for the development of contact dependent probiotics and novel anti-virulence therapeutics. Such cell-cell contact tracking assays may also subject to investigate the dynamics of intestinal colonization process and potential in vivo horizontal genes transfer.
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