Jennifer A. Philips, M.D., Ph.D.

Tuberculosis Pathogenesis and Immunity
Philips JA; Ernst JD
2011 Jan 25;:353-384, Annual review of pathology
Despite the development of potentially curative chemotherapy, tuberculosis (TB) continues to cause increasing worldwide morbidity and is a leading cause of human mortality in the developing world. Recent advances in bacterial molecular genetics, immunology, and human genetics have yielded insight into the molecular determinants of virulence, the immune responses that are essential for restricting progressive disease, and the determinants of immunopathology in TB. Despite these advances, a large knowledge gap still exists that limits the development and testing of new interventions, including novel drugs and efficacious vaccines. This review focuses on our current knowledge of TB pathogenesis and immunity that has been derived from in vitro and in vivo studies. In addition, it highlights topics that need to be better understood to provide improved means of controlling TB worldwide. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 7 is January 24, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates
— id: 145546, year: 2011, vol: , page: 353, stat: Journal Article,

Directly observing therapy: a new view of drug tolerance in tuberculosis
Philips, Jennifer A; Ernst, Joel D
2011 Apr 1;145(1):13-14, Cell
Drug tolerance in bacteria is widely believed to be due to metabolic changes that accompany growth arrest. A study in this issue of Cell reveals a drug tolerance mechanism in replicating mycobacteria that is induced by residence in macrophages and depends on drug efflux
— id: 130308, year: 2011, vol: 145, page: 13, stat: Journal Article,

Mycobacterial manipulation of vacuolar sorting
Philips, Jennifer A
2008 Dec;10(12):2408-2415, Cellular microbiology
Approximately one-third of the world's population is infected with Mycobacterium tuberculosis, and the World Health Organization estimates 1.6 million deaths were caused by M. tuberculosis in 2005. The enormous worldwide burden of disease underscores the proficiency by which M. tuberculosis is able to evade eradication by the host, subverting innate and adaptive defences. At the cellular level, mycobacteria are able to modulate macrophage defences by altering phagosome maturation. This review focuses on the bacterial proteins and lipids that are important in establishing the mycobacterial replicative niche. While there is a detailed molecular description of the vacuole and an increasing number of bacterial effectors have been implicated in creating this compartment, exactly how they intersect host cell processes remains ill-defined. However, the emerging picture is that an array of lipid and protein effectors collaborate to create and maintain the mycobacterial phagosome
— id: 91720, year: 2008, vol: 10, page: 2408, stat: Journal Article,

ESCRT factors restrict mycobacterial growth
Philips, Jennifer A; Porto, Maura C; Wang, Hui; Rubin, Eric J; Perrimon, Norbert
2008 Feb 26;105(8):3070-3075, Proceedings of the National Academy of Sciences of the United States of America
Nearly 1.7 billion people are infected with Mycobacterium tuberculosis. Its ability to survive intracellularly is thought to be central to its success as a pathogen, but how it does this is poorly understood. Using a Drosophila model of infection, we identify three host cell activities, Rab7, CG8743, and the ESCRT machinery, that modulate the mycobacterial phagosome. In the absence of these factors the cell no longer restricts growth of the non-pathogen Mycobacterium smegmatis. Hence, we identify factors that represent unique vulnerabilities of the host cell, because manipulation of any one of them alone is sufficient to allow a nonpathogenic mycobacterial species to proliferate. Furthermore, we demonstrate that, in mammalian cells, the ESCRT machinery plays a conserved role in restricting bacterial growth
— id: 91700, year: 2008, vol: 105, page: 3070, stat: Journal Article,

Torsades de pointes associated with voriconazole use
Philips, J A; Marty, F M; Stone, R M; Koplan, B A; Katz, J T; Baden, L R
2007 Mar;9(1):33-36, Transplant infectious disease
We describe 2 patients who developed prolonged QTc interval on electrocardiogram while being treated with voriconazole. The first patient had undergone induction chemotherapy for acute myelogenous leukemia, and her course had been complicated by invasive aspergillosis and an acute cardiomyopathy. She developed torsades de pointes 3 weeks after starting voriconazole therapy. She was re-challenged with voriconazole without recurrent QTc prolongation or cardiac dysfunction. The second patient had a significantly prolonged QTc interval while on voriconazole therapy. We recommend careful monitoring for QTc prolongation and arrhythmia in patients who are receiving voriconazole, particularly those who have significant electrolyte disturbances, are on concomitant QT prolonging medications, have heart failure such as from a dilated cardiomyopathy, or have recently received anthracycline-based chemotherapy. The potential for synergistic cardiotoxicity must be carefully considered
— id: 92781, year: 2007, vol: 9, page: 33, stat: Journal Article,

Genome-wide RNAi screen for host factors required for intracellular bacterial infection
Agaisse, Herve; Burrack, Laura S; Philips, Jennifer A; Rubin, Eric J; Perrimon, Norbert; Higgins, Darren E
2005 Aug 19;309(5738):1248-1251, Science
Most studies of host-pathogen interactions have focused on pathogen-specific virulence determinants. Here, we report a genome-wide RNA interference screen to identify host factors required for intracellular bacterial pathogenesis. Using Drosophila cells and the cytosolic pathogen Listeria monocytogenes, we identified 305 double-stranded RNAs targeting a wide range of cellular functions that altered L. monocytogenes infection. Comparison to a similar screen with Mycobacterium fortuitum, a vacuolar pathogen, identified host factors that may play a general role in intracellular pathogenesis and factors that specifically affect access to the cytosol by L. monocytogenes
— id: 91618, year: 2005, vol: 309, page: 1248, stat: Journal Article,

Drosophila RNAi screen reveals CD36 family member required for mycobacterial infection
Philips, Jennifer A; Rubin, Eric J; Perrimon, Norbert
2005 Aug 19;309(5738):1251-1253, Science
Certain pathogens, such as Mycobacterium tuberculosis, survive within the hostile intracellular environment of a macrophage. To identify host factors required for mycobacterial entry and survival within macrophages, we performed a genomewide RNA interference screen in Drosophila macrophage-like cells, using Mycobacterium fortuitum. We identified factors required for general phagocytosis, as well as those needed specifically for mycobacterial infection. One specific factor, Peste (Pes), is a CD36 family member required for uptake of mycobacteria, but not Escherichia coli or Staphylococcus aureus. Moreover, mammalian class B scavenger receptors (SRs) conferred uptake of bacteria into nonphagocytic cells, with SR-BI and SR-BII uniquely mediating uptake of M. fortuitum, which suggests a conserved role for class B SRs in pattern recognition and innate immunity
— id: 91619, year: 2005, vol: 309, page: 1251, stat: Journal Article,

Identification of Kel1p, a kelch domain-containing protein involved in cell fusion and morphology in Saccharomyces cerevisiae
Philips, J; Herskowitz, I
1998 Oct 19;143(2):375-389, Journal of cell biology
We showed previously that protein kinase C, which is required to maintain cell integrity, negatively regulates cell fusion (Philips, J., and I. Herskowitz. 1997. J. Cell Biol. 138:961-974). To identify additional genes involved in cell fusion, we looked for genes whose overexpression relieved the defect caused by activated alleles of Pkc1p. This strategy led to the identification of a novel gene, KEL1, which encodes a protein composed of two domains, one containing six kelch repeats, a motif initially described in the Drosophila protein Kelch (Xue, F., and L. Cooley. 1993. Cell. 72:681- 693), and another domain predicted to form coiled coils. Overexpression of KEL1 also suppressed the defect in cell fusion of spa2Delta and fps1Delta mutants. KEL2, which corresponds to ORF YGR238c, encodes a protein highly similar to Kel1p. Its overexpression also suppressed the mating defect associated with activated Pkc1p. Mutants lacking KEL1 exhibited a moderate defect in cell fusion that was exacerbated by activated alleles of Pkc1p or loss of FUS1, FUS2, or FPS1, but not by loss of SPA2. kel1Delta mutants form cells that are elongated and heterogeneous in shape, indicating that Kel1p is also required for proper morphology during vegetative growth. In contrast, kel2Delta mutants were not impaired in cell fusion or morphology. Both Kel1p and Kel2p localized to the site where cell fusion occurs during mating and to regions of polarized growth during vegetative growth. Coimmunoprecipitation and two-hybrid analyses indicated that Kel1p and Kel2p physically interact. We conclude that Kel1p has a role in cell morphogenesis and cell fusion and may antagonize the Pkc1p pathway
— id: 92779, year: 1998, vol: 143, page: 375, stat: Journal Article,

Osmotic balance regulates cell fusion during mating in Saccharomyces cerevisiae
Philips, J; Herskowitz, I
1997 Sep 8;138(5):961-974, Journal of cell biology
Successful zygote formation during yeast mating requires cell fusion of the two haploid mating partners. To ensure that cells do not lyse as they remodel their cell wall, the fusion event is both temporally and spatially regulated: the cell wall is degraded only after cell-cell contact and only in the region of cell-cell contact. To understand how cell fusion is regulated, we identified mutants defective in cell fusion based upon their defect in mating to a fus1 fus2 strain (Chenevert, J., N. Valtz, and I. Herskowitz. 1994. Genetics 136:1287-1297). Two of these cell fusion mutants are defective in the FPS1 gene, which codes for a glycerol facilitator (Luyten, K., J. Albertyn, W.F. Skibbe, B.A. Prior, J. Ramos, J.M. Thevelein, and S. Hohmann. 1995. EMBO [Eur. Mol. Biol. Organ.] J. 14:1360-1371). To determine whether inability to maintain osmotic balance accounts for the defect in cell fusion in these mutants, we analyzed the behavior of an fps1Delta mutant with reduced intracellular glycerol levels because of a defect in the glycerol-3-phosphate dehydrogenase (GPD1) gene (Albertyn, J., S. Hohmann, J.M. Thevelein, and B.A. Prior. 1994. Mol. Cell. Biol. 14:4135-4144): deletion of GPD1 partially suppressed the cell fusion defect of fps1 mutants. In contrast, overexpression of GPD1 exacerbated the defect. The fusion defect could also be partially suppressed by 1 M sorbitol. These observations indicate that the fusion defect of fps1 mutants results from inability to regulate osmotic balance and provide evidence that the osmotic state of the cell can regulate fusion. We have also observed that mutants expressing hyperactive protein kinase C exhibit a cell fusion defect similar to that of fps1 mutants. We propose that Pkc1p regulates cell fusion in response to osmotic disequilibrium. Unlike fps1 mutants, fus1 and fus2 mutants are not influenced by expression of GPD1 or by 1 M sorbitol. Their fusion defect is thus unlikely to result from altered osmotic balance
— id: 92780, year: 1997, vol: 138, page: 961, stat: Journal Article,

Perturbation of nuclear architecture by long-distance chromosome interactions
Dernburg, A F; Broman, K W; Fung, J C; Marshall, W F; Philips, J; Agard, D A; Sedat, J W
1996 May 31;85(5):745-759, Cell
SUMMARY: Position-effect variegation (PEV) describes the stochastic transcriptional silencing of a gene positioned adjacent to heterochromatin. Using FISH, we have tested whether variegated expression of the eye-color gene brown in Drosophila is influenced by its nuclear localization. In embryonic nuclei, a heterochromatic insertion at the brown locus is always spatially isolated from other heterochromatin. However, during larval development this insertion physically associates with other heterochromatic regions on the same chromosome in a stochastic manner. These observations indicate that the brown gene is silenced by specific contact with centromeric heterochromatin. Moreover, they provide direct evidence for long-range chromosome interactions and their impact on three-dimensional nuclear architecture, while providing a cohesive explanation for the phenomenon of PEV
— id: 92778, year: 1996, vol: 85, page: 745, stat: Journal Article,

Cysteine protease inhibitors block schistosome hemoglobin degradation in vitro and decrease worm burden and egg production in vivo
Wasilewski, M M; Lim, K C; Phillips, J; McKerrow, J H
1996 Oct 30;81(2):179-189, Molecular & biochemical parasitology
Schistosome parasites utilize hemoglobin as a major protein source for their metabolism. Degradation of hemoglobin has been hypothesized to be mediated by both cysteine and aspartyl proteases secreted into the lumen of the parasite intestine. We now show that two distinct types of irreversible cysteine protease-specific inhibitors both arrest schistosome hemoglobin degradation in vitro. Arrest of hemoglobin degradation is followed by death of developing schistosomula 1 week later. Schistosome infected mice treated by a dose of 2 mg inhibitor per day for 1 week early in infection, and 2 weeks at the time of egg production, showed a significant reduction in worm burden, hepatomegaly, and the number of eggs produced per female worm. Histopathology showed a minimal immune response to those eggs which were produced, consistent with a delay in egg production relative to untreated infections. By tagging the inhibitor with biotin, specific cysteine protease targets were identified in extracts of schistosome worms
— id: 92782, year: 1996, vol: 81, page: 179, stat: Journal Article,

Comparison of the expression of the seven ribosomal RNA operons in Escherichia coli
Condon, C; Philips, J; Fu, Z Y; Squires, C; Squires, C L
1992 Nov;11(11):4175-4185, EMBO journal
We have compared the expression of the seven ribosomal RNA operons (rrn) of Escherichia coli and their responses to a variety of physiological and genetic perturbations. We used a set of rrn promoter fusion constructs in their native chromosomal positions to examine effects of chromosomal location on rrn operon expression and the same set of fusions on lambda lysogens to assay intrinsic promoter strengths independent of chromosome context. In its native chromosomal location, expression of the rrnH operon was significantly lower than expected. This effect was not attributable to weak promoter activity and was dependent on the growth medium. The rrnE operon had reduced promoter activity relative to the other ribosomal operons in minimal medium and thus appears to have abnormal growth rate regulation. The ribosomal RNA operons showed varied responses to amino acid starvation; expression of rrnD was inhibited most. There was only a slight increase in rrn transcription in response to a temperature shift (30 degrees C to 42 degrees C) and the differences between individual operons was very small. The rrnG operon showed a significantly lower response than the other ribosomal RNA operons to a depletion of the rrn transcription activator, Fis, and thus appears to have decreased Fis-mediated transactivation. Finally, the chromosomal fusion strains were used to study the effect on growth rate of inactivating each rrn operon. In fast growth conditions, loss of certain rrn operons caused subtle decreases in growth rate on complex medium
— id: 92777, year: 1992, vol: 11, page: 4175, stat: Journal Article,