Biochemistry and Molecular Biology
Co-Head of the Laboratory of Tumor Cell Biology-Institute of Human Virology Member, Program in Tumor Immunology and Immunotherapy, Greenebaum Comprehensive Cancer Center
725 W. Lombard Street N458
Education and Training
1987: PhD: Biological Sciences, University of Pavia, Italy.
1989-1992: Post Doctoral fellow: National Research Council, Pavia, Italy.
1992-1995: Guest Researcher: Laboratory of Tumor Cell Biology, NCI, NIH, Bethesda, MD.
After completing his Ph.D. and post doctoral training, Dr. Davide Zella joined the Laboratory of Dr. R.C. Gallo at the National Institutes of Health in Bethesda, Maryland. Subsequently he followed Dr. RC. Gallo and joined the Institute of Human Virology and the School of Medicine at the University of Maryland, Baltimore. Dr. Davide Zella has more than 25 years of experience in the field of microbiology/virology, immunology, cancer biology and molecular biology. He has more than 50 publications, including peer reviewed articles and books chapters. Early in his career, Dr. Zella studied the interactions between IFN-alpha and the immuno-system, in particular the anti-proliferative ability of IFN-alpha, the regulation of chemokine receptors by Interferons, and mechanisms of intracellular replication of HIV. Previous focus of Dr Zella's research has been done is collaboration with Professor Lu’s laboratory, leading to the characterization of the interactions between p53 and its antagonists (MDM2 and MDMX). In fact, inhibition of p53 through interaction with these antagonists is observed in about 50% of cancers, even though P53 is fully functional. Indeed, activation of p53 results in some cases in partial reduction of cancer cells number. Aim of the study was to design peptides able to block such interaction, thus reactivating p53.Currently the Lab is studying the mechanism(s) of cellular transformation following interactions between components of the human microbiota and their host cells. We demonstrated that a strain of Mycoplasma promotes lymphomagenesis in an in vivo mouse model; and that a bacterial chaperone protein, DnaK, is implicated in the transformation process and resistance to anti-cancer drugs, by interfering with important pathways related to both DNA-damage control/repair and cell-cycle/apoptosis. Other tumor-associated bacteria carry a similar DnaK protein. Our data suggest a common mechanism whereby bacteria can be involved in cellular transformation and resistance to anti-cancer drugs by a hit and hide/run mechanism. The Lab has also been recently involved is the analysis of SARS-CoV-2 genome and its mutations, with the aim of identifying potential targets of diagnostic/therapeutic intervention.
Cancer biology, p53, microbiota, Mycoplasma.
- Benedetti F. Curreli S, Zella D. Mycoplasmas-Host interaction: mechanisms of inflammation and association with cellular transformation. (2020) Microorganisms, 8(9), E1351, 2020. doi: 10.3390/microorganisms8091351
- Benedetti F, Cocchi F, Latinovic OS, Curreli S, Krishnan S, Munawwar A, Gallo RC, Zella D (2020). Role of mycoplasma chaperone DnaK in cellular transformation. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, ISSN: 1422-0067, doi: doi: 10.3390/ijms21041311
- Zella D*, Curreli S, Benedetti F, Krishnan S, Cocchi F, Latinovic OS, Denaro F, Romerio F, Djavani M, Charurat ME, Bryant JL, Tettelin H, Gallo RC* (2018). Mycoplasma promotes malignant transformation in vivo, and its DnaK, a bacterial chaperone protein, has broad oncogenic properties. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, ISSN: 0027-8424, doi: 10.1073/pnas.1815660115 * Corresponding authors
- Ademamowo SA, Ma B, Zella D, Famooto A, Ravel J, Ademamowo C, and ACCME Research Group. (2017). Mycoplasma hominis and Mycoplasma genitalium in the vaginal microbiota and persistent high-risk human papillomavirus infection. FRONTIERS IN PUBLIC HEALTH, ISSN: 2296-2565, doi: 10.3389/fpubh.2017.00140
- Benedetti F, Snyder GA, Giovanetti M, Angeletti S, Gallo RC, Ciccozzi M*, Zella D* (2020). Emerging of a SARS-CoV-2 viral strain with a deletion in nsp1. JOURNAL OF TRANSLATIONAL MEDICINE, vol. 18, ISSN: 1479-5876, doi: 0.1186/s12967-020-02507-5* Corresponding authors
- Pachetti M, Marini B, Giudici F, Benedetti F, Angeletti S, Ciccozzi M, Masciovecchio C, Ipprodrino R, Zella D. Impact of lockdown on Covid-19 Case Fatality Rate and Viral Mutations Spread. JOURNAL OF TRANSLATIONAL MEDICINE, 18 (1) 338, 2020. doi: 10.1186/s12967-020-02501-x.Benedetti F, Pachetti M, Marini B, Ippodrino R Ciccozzi M*, Zella D* (2020). SARS-Cov-2: March toward adaptation. JOURNAL OF MEDICAL VIROLOGY, ISSN: 0146-6615, doi: 10.1002/jmv.26233. Corresponding authors.
- Pachetti M, Marini B, Giudici F, Benedetti F, Angeletti S, Ciccozzi M, Masciovecchio C, Ippodrino R, Zella D. (2020). Impact of lockdown on Covid-19 case fatality rate and viral mutations spread in 7 countries in Europe and North America. JOURNAL OF TRANSLATIONAL MEDICINE, vol. 18, ISSN: 1479-5876, doi: 0.1186/s12967-020-02501-x
- Pachetti M, Marini B, Benedetti F, Giudici F, Mauro, E, Storici P, Masciovecchio C, Angeletti S, Ciccozzi M, Gallo RC, Zella D*, Ippodrino R* (2020). Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant. JOURNAL OF TRANSLATIONAL MEDICINE, ISSN: 1479-5876, doi: 10.1186/s12967-020-02344-6. * Corresponding authors
Studies on association between Microbiota and cellular transformation
- In our seminal studies, we isolated and characterized a strain of human Mycoplasma fermentans able to induce lymphoma in a Severe Combined Immuno-Deficient (SCID) mouse model, similar to a previously described lymphomagenesis dependent upon reduced p53 activity. Mycoplasma was abundantly detected early in infected mice, but only low copy numbers of Mycoplasma DnaK DNA sequences were found in primary and secondary tumors, suggesting a “hit and run/hide” mechanism of transformation, in which the critical events have occurred previous to cancer detection. We demonstrated that this Mycoplasma’s DnaK binds to human USP10 (ubiquitin carboxyl-terminal hydrolase 10, a regulator of p53 stability), reducing p53 stability and anti-cancer functions, potentially increasing the likelihood of DNA mutations and consequent malignant transformation. By removing conjugated ubiquitin from target proteins, including p53, USP10 increases p53 stability in unstressed cells. This process is very important during DNA-damage response, in which USP10 translocates to the nucleus and deubiquitinates p53, stabilizing it and thus regulating its response to DNA damage. It is thus clear that the reduction in USP10 activity caused by Mycoplasma DnaK can have profound negative effects on the anti-cancer functions of p53 (Zella D. et al., PNAS, 2018). We also showed that Mycoplasma DnaK reduced PARylation activity of PARP1 following DNA damage. PARP 1 is one of the most studied members of the family of PARP proteins, involved in the recognition and subsequent repair of single and double-strand breaks in DNA. Following interaction with forms of damaged DNA, PARP1 activity is increased dramatically, resulting in PARylation of several proteins, including itself, histones, topoisomerase 1 (TOP1), DNA-dependent protein kinase (DNA-PK) and others factors to the damaged site. Failure to properly repair DNA damage usually results in apoptosis, thus avoiding accumulation of DNA damage that could ultimately lead to cellular transformation.
- Given its ability to bind USP10 and reduce p53 stability and activities, it is conceivable that Mycoplasma DnaK can counteract the efficacy of other compounds that depend upon increased p53 activity for their anti-cancer effect. To test this hypothesis, we treated HCT116 adenocarcinoma and AGS (a stomach cancer cell line) with platinum-based compounds (Cisplatin and Carboplatin), that exert their anti-cancer effect through p53 activation. As expected, treatment with the anti-cancer drugs caused a marker reduction in the number of viable cells. When the cells were treated with exogenous DnaK we observed increased resistance to both drugs. To further validate that DnaK was responsible for this effect, we used a peptide (ARV-1502, optimized from A3-APO) which has been previously demonstrated to bind to E. coli DnaK substrate-binding domain and to reduce its ATPase activity. In the presence of ARV-1502, there was a statistically significant reversal of the effect of Mycoplasma DnaK on anti-cancer drugs. We confirmed binding of the peptide to Mycoplasma DnaK and entry of Mycoplasma DnaK into the cancer cell lines. These data demonstrate that DnaK is responsible for reducing the effect of p53-dependent drugs in select cancer cell lines, and this effect is reversed by a peptide able to bind Mycoplasma DnaK to its substrate binding domain and able to block its ATPase activity;
- we are currently studying the effect of DnaK on cellular transformation in an in vivo model of DnaK knock-in mouse designed in our laboratory. DnaK was inserted at the locus of ROSA26 in C57BL/6 mice by CRISPR/Cas-mediated genome editing. The DnaK gene is under the control of the CMV promoter for constitutive expression and carries a V5 Tag for convenient detection. It is important to note that our previous results in vitro show that the V5 tag does not affect the ability of DnaK to reduce protein binding or p53-dependent anti-cancer activities.
The Lab has been also recently involved is the analysis of SARS-CoV-2 genome and its mutations, with the aim of identifying potential targets of diagnostic/therapeutic intervention.
- By analyzing a subset of complete SARS-CoV-2 genomic sequences from COVID-19 patients deposited in the GISAID database, our group was among the first to identify the appearance in COVID-19 patients of a viral variant with mutations in the RNA polymerase catalytic subunit (nsp12) and Spike protein (D614G) clustered together, which eventually became the dominant viral strain both in Europe and in the USA (Pachetti M. et al., J. Transl. Med., 2020). Coronaviruses use an RNA-dependent RNA polymerase (RdRp) complex composed of a catalytic subunit, nsp12 and two accessory proteins, nsp7 and nsp8, to replicate their genomes. SARS-CoV-2 RdRp shares a high homology with the RdRp of SARS-CoV, suggesting that function and mechanism of action are conserved between the two complexes. Since mutations in the polymerase complex can lead to drug resistance, it is important to characterize SARS-CoV-2 RNA polymerase mutations to identify possible drug resistant viral phenotypes.
- We demonstrated a correlation between high temperatures and reduced mortality rates of COVID-19 patients. Our data indicate that social distancing measures are more successful in the presence of higher average monthly temperatures in reducing COVID-19-related death rate, and a high level of population density seems to negatively impact the effect of lockdown measures (Benedetti F. et al., J. Transl. Med, 2020).
- We also very recently identified a deletion in the non structural protein-1 (nsp1) of SARS-CoV-2. Nsp1 is arguably the most important pathogenic determinant, and previous studies on SARS-CoV indicate that it is both involved in viral replication and hampering the innate immune system response. This deletion was found widespread through different geographical areas. Structural prediction modelling suggests an effect on the C-terminal tail structure and indicates that the virus is undergoing profound genomic changes, most likely becoming less pathogenic (Benedetti F. et al., submitted). If our hypothesis is correct, we should find a prevalence of this viral strain in asymptomatic and pauci-symptomatic subjects.
- Associate Editor for Infectious Diseases-Frontiers in Microbiology.
- Associate Editor for Molecular and Cellular Oncology – Frontiers in Cell and developmental Biology and Frontiers in Oncology.
- Guest Associate Editor for Evolutionary and Population genetics - Frontiers in Genetics and Frontiers in Ecology and Evolution: Topic: "Source-tracking”, molecular epidemiology and antigenic diversity of SARS-CoV-2 infections causing coronavirus disease 2019, COVID-19.5 (IF 2019); 3.6 IF (3 years). JCR Q1
- Section Editor: Journal of Translational Medicine –Immunovirology section.
- Topic Editor: International Journal of Molecular Sciences.
"Ad hoc" reviewer (Funding Agencies):
- French National Research Agency (current)
- National Science Center, Poland (current)