Research Focus

The overarching goal of the Sellati Laboratory is to understand how host responses are ‘tailored’ to the specific pathogens they encounter, particularly pathogens that represent emerging and re-emerging infectious bacterial and viral agents whose arthropod vector are ticks and mosquitoes. Studies in the laboratory focus on two distinct, yet interrelated aspects of bacterial and viral pathogenesis (i.e., disease development and resolution). In both instances, we believe innate immunity, a pre-programmed first-line defense against invading pathogens, plays a defining role in the disease process.

A fundamental question we hope to answer is why some infected individuals present with more severe and/or persistent inflammation and various disease symptoms than others. With such an answer in hand one can envision the development of vaccines and immunotherapeutic strategies to better prevent or combat infectious diseases in individuals, respectively.

Mechanism and consequences of bacterial recognition

Lyme disease and syphilis are acute and chronic inflammatory disorders caused by the spirochetal pathogens Borrelia burgdorferi and Treponema pallidum subsp. pallidum, respectively. Both spirochetes lack lipopolysaccharide (LPS); however, they do possess abundant membrane lipoproteins that are potent activators of monocytes/macrophages, neutrophils, lymphocytes, endothelial cells, and fibroblasts. Innate immune cells serve as a first-line defense against bacterial challenge by sensing invading pathogens via nonclonal pattern recognition receptors (PRR) that interact with microbial structures and deliver a danger signal to the host cell.

Much of the lab’s efforts over the past 15 years have been to characterize the role of CD14 in recognition of B. burgdorferi and initiation of appropriate host defenses during natural infection. Several years ago we reported that, contrary to an anticipated diminution in pathology (based upon in vitro cell-based studies using borrelial lysates and isolated Toll-Like Receptor 2 (TLR2) ligands), CD14-/- mice infected with B. burgdorferi exhibit more severe and persistent inflammation and impaired bacterial clearance than their wild-type (CD14+/+) counterparts. Next, we described how recognition of B. burgdorferi not only triggered an inflammatory response in the absence of CD14, but one that is a consequence of altered PI3K/AKT/p38 activity and impaired negative regulation of Toll-Like Receptor 2 (TLR2) signaling.

As depicted in the accompanying cartoon, CD14 deficiency results in supra-physiologic and prolonged expression of TLR2, increased localization of PI3K to lipid-rich detergent-resistant microdomains of the plasma membrane, hyper-phosphorylation of AKT, and reduced activation of p38. Such aberrant signaling leads to decreased negative regulation of NF-κB activity by SOCS, thereby compromising the induction of tolerance in macrophages and engendering more severe and persistent inflammatory responses to B. burgdorferi. In other studies we sought a mechanistic explanation for the observation that both the intensity and duration of Lyme arthritis varies widely in the human population. C3H/HeN and C57BL/6 mouse strains are the most and least susceptible to Lyme arthritis, respectively. In two interrelated studies we have observed that unlike in CD14-/- C3H/HeN mice where diminished SOCS activity leads to more severe and persistent disease (see cartoon above), in the disease-resistant C57BL/6 strain a negative regulatory pathway independent of SOCS is perturbed by the absence of CD14. In the C57BL/6 background, it was observed that CD14 deficiency results in decreased p38 activity, diminished production of the anti-inflammatory cytokine IL-10 and a dramatic increase in TNF, IFN-γ, and chemoattractants (e.g., CXCL9/10) that recruit highly-activated and destructive CD4+ T cells to the joint. Importantly, these altered signaling events and the higher proinflammatory cytokine production observed in the absence of CD14 appears to phenocopy the antibiotic-refractory hyper-inflammatory response recently reported in Lyme arthritis patients harboring a tlr1-1805GG polymorphism published in Arthritis and Rheumatism by Sterle et al. As described in our accompanying editorial, the hyper-inflammatory response that correlates with carriage of the tlr1-1805GG polymorphism is associated with the same decrease in p38 activity and bias towards production of IFN-γ rather than IL-10 and CXCL9/10 we observed in CD14-/- C57BL/6 mice infected with B. burgdorferi.

In addition to the seminal findings regarding the role of CD14 and TLR2 signaling in Lyme disease pathogenesis, it also was observed that genetic lesions that reduce or eliminate the presence of natural killer T (NKT) cells or γδ T cells at sites of infection also engender more severe and prolonged arthritis as well as reduce the efficiency of clearance of spirochetes. Specifically, in collaboration with Dr. Mitchell Kronenberg (President, La Jolla Institute of Allergy and Immunology, CA), we showed that Vα14i NKT (iNKT) cells are activated during B. burgdorferi infection. More importantly, our data demonstrated that iNKT cell antigen recognition is not confined to glycosphingolipids, but also includes diacylglycerols from pathogenic bacteria, suggesting the conserved T cell receptor of iNKT cells could play a role in host protection against a variety of microbes. Using a mouse model of Lyme arthritis we demonstrated, for the first time, that iNKT cells are important for the prevention of persistent joint inflammation and spirochete clearance, and that specific antibodies are unlikely to mediate these effects. In other experiments it was shown that a subset of Vδ1-expressing synovial T cells from Lyme arthritis patients could response to conserved B. burgdorferi lipoproteins. The conservation of these structures in other spirochetes suggests that Vδ1 cells may also be important T cell participants in innate immunity, potential examples being recognition of non-protein components of Mycobacterium tuberculosis by Vγ9Vδ2 cell and glycosylceramide by NK1.11 T cells.

In addition to elucidating the role of innate immune recognition of B. burgdorferi in Lyme disease pathogenesis these efforts have been extended to a study of CD14 and TLR2 signaling in tularemia pathogenesis. Caused by the CDC-designated Category “A” Select Agent, Francisella tularensis ssp. tularensis, the role of various PRRs in innate immunity to and the process of vaccination against F. tularensis has been a focus of the lab. Back in 2006 we and another group were the first to define a role for TLR2 in the host response to the Live Vaccine Strain and Select Agent SchuS4 strain of F. tularensis. The latter strain, being highly infectious and deadly for humans, can only be manipulated in a CDC-approved Animal Biosafety Level 3 (ABSL3)/BSL-3 containment facility. Though not the first to demonstrate the ability of TLR2 to mediate F. tularensis-induced cytokine release from macrophages in in vitro cell-based studies, we were the first to demonstrate a role for TLR2 in controlling pulmonary infection with F. tularensis using a mouse model of respiratory tularemia. Then, in collaboration with Drs. Karsten Hazlett, PhD and Edmund Gosselin, PhD, fellow colleagues in the Center for Immunology and Microbial Disease at Albany Medical College, we went on to characterize the consequences of mammalian host-adaptation of F. tularensis with respect to in vitro and in vivo innate cellular response and the ability to confer protective immunity to lethal challenge through vaccination. These studies included the first evidence that F. tularensis infection establishes a principally anti-inflammatory pulmonary environment typified by the presence of IL-10, TGFβ, and the presence of tolerogenic dendritic cells (tDCs) and regulatory T cells (Tregs). Moreover, upon adaptation to the mammalian environment F. tularensis is incapable of stimulating the release of select proinflammatory cytokines (e.g., TNF, IL-1β, IL-6, and IFN-γ), findings that were contrary to in vitro results dating back over a decade.


Continuing Efforts: Current efforts focus on experimentally determining the extent to which persistent arthritis [aka, Post Treatment Lyme Disease Syndrome (PTLDS)], perhaps associated with CD14-deficiency or the tlr1-1805GG polymorphism, reflects a bias towards expression of TLR2 homodimers rather than heterodimers on immune cells; a concept outlined in the editorial mentioned above and in the accompanying picture. This work is being done in collaboration with Allen Steere, MD (Massachusetts General Hospital). Additionally, experiments have been undertaken to explore the use of p38 inhibitors and/or cAMP analogs to reciprocally regulate pro- and anti-inflammatory cytokine production to alleviate the symptoms of PTLDS.

Currently we are building upon the foundational observation that NKT cells may play a critical role in modulating the severity and duration of Lyme arthritis. In collaboration with Dr. Jonathan Krant, MD (Rheumatologist, Adirondack Medical Center) and Mitchell Kronenberg we will be interrogating NKT cells collected from healthy adult donors, and Lyme arthritis and rheumatoid arthritis patients to determine whether differences in the cell’s proliferative capacity and activation status exist. If such differences exist, we then can explore whether differences also exist within cohorts of Lyme arthritis patients that segregate into treatment-responsive and -refractory groups.

Ongoing efforts also are defining the role of F. tularensis in modulating (i) neutrophil recruitment to the lung via activation of matrix metalloproteinase 9 (MMP-9) and (ii) host cell death programs via activation of the ALOX5-regulated eicosanoid pathway. This work has been continuously funded since 2003 through several competitive renewals of a PO1 Program Project Grant on which I was the Principle Investigator (PI) of Subproject 2, as well as an independent RO1 and, most recently, a multiple-PI RO1 that is conceptually centered around the importance of host-adaptation and whose goal is to refine a novel vaccine development platform to combat a wide variety of biological threat agents.

(funding support by Steven & Alexandra Cohen Foundation)

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Combatting antibiotic resistant bacterial infections

Many hospital-acquired infections are caused by Gram-negative bacterial pathogens, which are increasingly resistant to a wider range of available antibiotics. According to the CDC, treating such infections cost an estimated $45 billion annually. Effective response to this public health challenge necessitates adoption of an “outside-the-box” strategy for the de novo design of novel classes of microbicides.

Antimicrobial peptides (AMPs) are promising alternatives to conventional antibiotics due to their direct targeting of bacterial cell membranes, which are less prone to modification to avoid the action of bactericides. However, intrinsic limitations associated with conventional AMPs exist, including host cell cytotoxicity, protease susceptibility, and poor penetration of the host cell’s plasma membrane to eliminate intracellular pathogens. In collaboration with Dr. He Dong, PhD, a chemist at Clarkson University in the Department of Chemistry and Biomolecular Sciences, we have developed a novel self-assembling antimicrobial nanofiber (SAAN) technology for safer and more effective therapeutic administration of AMPs compared to conventional treatment options.

SAANs, the ‘nucleus’ of our antimicrobial therapeutic platform, are supramolecular assemblies of de novo designed β-sheet-forming multi-domain peptides (MDPs) with a general formula of Kx(QL)yKz (amino acid single code letter K: Lysine, Q: Glutamine, L: Leucine). The accompanying cartoon shows the representative chemical structure of an MDP when in monomeric form as well as when self-assembled into a nanofiber (Red: leucine; Green: glutamine; Grey: lysine). MDPs contain a central (QL) repeating domain possessing alternating hydrophilic (Q) and hydrophobic (L) amino acids; such alternating patterns provide strong intermolecular hydrogen bonding forces for peptides to fold into β-sheet secondary structures. Compared to single peptide chains, large-scale supramolecular peptide assemblies have distinctive modes of cellular interaction that can be tuned by adjusting peptide primary sequences and thus the intermolecular interactions between individual peptide chains. Our group reported on the cell penetration activity of two cationic MDPs that differ in their ability to self-assemble into supramolecular nanofibers. These nanofiber-forming peptides also show dramatically enhanced cell uptake and stability in serum, protease resistance with D-amino acid substitution for L-amino acids, and pan-bactericidal activity against both Gram-negative and -positive pathogens. The accompanying electron microscopic images depict the severe damage caused by MDP-2 to the structural integrity of Acinetobacter baumannii (a.k.a., “Iraqi-bacter”), a highly drug resistant pathogen often colonizing deep tissue wounds suffered by soldiers during the wars in Iraq and Afghanistan. Untitled

Continuing Efforts: Currently we are synthesizing and assembling new MDPs that contain (1) non-natural D-amino acids to further increase resistance to proteolysis; (2) cell-penetrating peptides (CPPs) to increase their antimicrobial activity; and potentially (3) functional polymers [e.g., polyethylene glycol (PEG)] to generate SAANs with improved stability required for prolonged storage and product application. The nanostructure of these newly synthesized SAANs are being characterized and evaluated for their resistance to proteolysis in the presence of trypsin, α-chymotrypsin, and S. griseus-derived proteases. In addition, the ability of SAANs to inhibit the growth of bacteria using two clinical isolates of Colistin-susceptible and -resistant A. baumannii, is being assessed as well as the selectivity of effect on prokaryotic versus eukaryotic membranes. Finally, all SAANs formulations are being tested and refined in an iterative fashion to identify those optimized for little or no in vitro and in vivo cytotoxicity and reactigenicity.   Lead candidates will be advanced through toxicological and pharmacokinetic evaluation in animal studies that will be conducted in accordance with the standards of 21 CFR Part 58 “Good Laboratory Practices” to ensure that the resulting animal model results meet the requirements for first line investigation and subsequent FDA approval of novel therapeutics.

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Viral infection and neurodegenerative diseases

Prior to 2015, outbreaks of Zika virus (ZIKV, genus flavivirus; family Flaviviridae) occurred in regions of Africa, Southeast Asia, and the Pacific Islands resulting in mild symptoms most commonly including fever, rash, arthralgia and myalgia, and conjunctivitis that last for several days to a week. In May of 2015, the first confirmed case of ZIKV infection was reported in Brazil and the virus has quickly spread across 23 countries and territories in the Americas reaching the borders of the United States. Concurrent with the introduction and spread of ZIKV there has been an increased incidence of cases of Guillain-Barré syndrome, a form of peripheral nerve paralysis, and pregnant women giving birth to babies with microcephaly, a developmental disorder characterized by an abnormally small head and severe reduction in brain size, due primarily to interruption of normal growth of the cerebral cortex. According to the World Health Organization, in Brazil alone, more than 4,000 suspected cases of microcephaly have been documented and potentially linked to ZIKV infection. Intriguingly, there is a report of ZIKV being isolated during post-abortion autopsy of a fetus’ brain (

A number of other flaviviruses (e.g., Dengue, Japanese encephalitis virus, and West Nile virus) are known to cause neurological symptoms in humans and Dick et al. demonstrated ZIKV tropism for the central nervous system (CNS) in intraperitoneally-infected mice, suggesting the virus can cross the blood brain barrier. Subsequently, Bell et al. demonstrated via intracerebral inoculation that ZIKV targets neurons and glia within the mouse CNS. Based on these observations, combined with reports of perinatal transmission of ZIKV in humans and increased incidence and/or case reporting of microcephaly, there is a strong possibility that ZIKV can cause microcephaly as well as other neuropathies in humans. However, to date, a direct and unequivocal causative link between ZIKV infection in pregnant mothers and microcephaly in developing fetuses has yet to be established. Given the serious nature of microcephaly, especially its significant neurological and developmental/behavioral consequences, answers are urgently needed so that informed decisions and rational steps can be taken to appropriately identify and protect at-risk populations, and effective countermeasures against ZIKV infection can be instituted. Additionally, animal models that can effectively recapitulate this special population of at risk individuals are greatly needed to demonstrate the protective efficacy of candidate antiviral therapeutics. 

Given the critical knowledge gaps described above, the overarching goal of this research program is to develop and employ pertinent animal models [i.e., mouse and non-human primate (NHP)] to: (i) establish whether a causative link exists between ZIKV infection of pregnant mothers and neuropathies (e.g., microcephaly) in developing fetuses, and (ii) decipher the cellular and molecular mechanism(s) of ZIKV-induced neuropathy. These two important objectives will be achieved by validating 1) whether progression of ZIKV in pregnant mice challenged at different times during gestation impacts both the dams and their unborn fetuses, 2) whether ZIKV dysregulates host cell microRNA (miR) function responsible for proper growth and development of the cerebral cortex of mice and NHPs, and 3) whether ZIKV invasion of the CNS elicits inflammatory cross-talk between cell types that provokes neuropathy.


Figure 1. Inhibition of miR-7 (7-sp) causes microcephaly.

Efforts are underway to propagate various isolates of ZIKV and use them in studies characterizing the miR and inflammatory response of isolated neural progenitor cells, in vitro 3-D ‘cerebral organoid’ cultures, and murine dams and their fetuses. The rationale for focusing on host miRs derives from the fact that precise regulation of gene expression is required for proper growth and development of the cerebral cortex. Dysregulation of gene expression within the CNS results in developmental defects such as microcephaly. Recent evidence suggests the action of miRs ensures proper neural stem cell proliferation, survival, differentiation, and migration during development of the cerebral cortex. Emerging evidence shows that miR-7 is essential for cortical neural progenitor cell function, and its blockade causes microcephaly-like brain defects in mice (Figure 1). Tangentially, viral infection can exert a profound impact on the expression profile of miRs, and several RNA viruses, of which ZIKV is one, have been reported to interact directly with host miRs to augment viral replication. ZIKV can cross the blood-brain barrier in mice and humans, as well as the placenta in humans. Infection of both neurons and glia of mice creates intracytoplasmic inclusions termed ‘virus factories’. Ultimately, a better understanding of Zika pathogenesis and knowledge of if and how infection incites the development of neuropathology will serve as the foundation for the development of novel vaccines and therapeutic strategies to combat this latest world-wide viral threat to human health.


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Tim Sellati

Senior Research Fellow and Chair, Infectious Diseases Department

Timothy Sellati, Ph.D., is a senior research fellow and the chair of Southern Research’s Infectious Diseases Department. Sellati leads infectious disease researchers who are currently working to identify novel mechanisms, targets, and strategies for prevention and treatment of both bacterial and viral infectious diseases that occur throughout the world. [ Read Full Bio Here ]

Lab Members

Shiva Kumar Goud Gadila, M.S.

Shiva Kumar Goud Gadila, M.S.

Associate Biologist

Shiva Kumar Goud Gadila received his Bachelor’s of Science in Pharmacy from Jawaharlal Nehru Technological University, Hyderabad, India, in 2012. In 2013, he joined Dr. Kyoungtae Kim’s lab at Missouri State University, Springfield, Missouri, to pursue his Master’s. During his graduate studies, he focused his research on studying intracellular trafficking of proteins and protein-protein interactions. Later, he worked as a drug safety specialist for Pharmaceutical Product Development (PPD). In November of 2016, he joined Southern Research to work in Dr. Sellati’s lab as an Associate Biologist.

Fahim Ahmad, Ph.D.

Fahim Ahmad, Ph.D.

Post-Doctoral Researcher

Dr. Fahim Ahmad obtained his B.S. with honors and an M.S. degree in Biotechnology. Dr. Ahmad next completed his Ph.D. in Molecular Genetics from University of Bundelkhand, Jhansi, India. He completed his first postdoctoral training in the Department of Microbiology and Immunology at the Indiana University School of Medicine in Indianapolis, where his research efforts as a virologist focused on understanding how interaction of HIV-1 (AIDS virus) envelope glycoproteins with host cell receptors leads to membrane fusion and viral entry. He completed his second postdoctoral training at Texas Tech University in El Paso, Texas, where his research focused on the mechanisms of genetic resistance to HIV-1 infection. Later, he joined the University of Texas in El Paso as a Research Scientist and Lecturer where he taught Cellular Immunology at the graduate level and carried out research on T cell-mediated immune control of persistent HIV infection for the purpose of vaccine design. Dr. Ahmad joined Southern Research in 2014. His overall goal is to identify new therapies that target influenza viral replication. A primary concern with the current drugs (amantadines and neuraminidase inhibitors) used to treat influenza is the development of resistant mutations that negate therapeutic benefit. The hypothesis underlying his current research efforts is that compounds that specifically target the polymerase complex might reduce the frequency of escape mutations or promote escape mutants that are unfit for replication. Dr. Ahmad is a member of the Board of Directors for the Integrated Biotechnological Research Institute, is a member of several editorials boards, and serves as a peer reviewer for scientific journals such as General Medical Virology and Center for Neurological Disorders & Drug Targets.

Yohanka Martinez-Gzegozewska, M.S.

Yohanka Martinez-Gzegozewska, M.S.


Yohanka Martinez-Gzegozewska holds a bachelor’s degree in Biochemistry, and a Master’s degree in Protein Biochemistry, both from the School of Biology, University of Havana, Cuba. During her Master’s degree training she undertook a research project for her thesis work characterizing immunoadjuvant properties of liposomes. Specifically, she studied the ability of liposomes to enhance the immune response against human recombinant epidermal growth factor (hrEGF) for its use as a therapeutic vaccine for the treatment of breast tumors overexpressing EGF. In 2006, she joined the Cuban National Regulatory Authority of Drugs, where she worked as a specialist for the evaluation of the quality and approval of biomolecules for clinical trials or marketing. She came to the United States in 2013, and joined the Drug Discovery Division of Southern Research in April 2014 as a Biologist. She is currently involved in drug discovery efforts against Influenza, wherein she is helping in the identification of small molecule anti-Influenza virus drug candidates.

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