Effective, broad spectrum control of virulent bacterial infections using cationic DNA liposome complexes combined with bacterial antigens.
Protection against virulent pathogens that cause acute, fatal disease is often hampered by development of microbial resistance to traditional chemotherapeutics. Further, most successful pathogens possess an array of immune evasion strategies to avoid detection and elimination by the host. Development of novel, immunomodulatory prophylaxes that target the host immune system, rather than the invading microbe, could serve as effective alternatives to traditional chemotherapies. Here we describe the development and mechanism of a novel pan-anti-bacterial prophylaxis. Using cationic liposome non-coding DNA complexes (CLDC) mixed with crude F. tularensis membrane protein fractions (MPF), we demonstrate control of virulent F. tularensis infection in vitro and in vivo. CLDC+MPF inhibited bacterial replication in primary human and murine macrophages in vitro. Control of infection in macrophages was mediated by both reactive nitrogen species (RNS) and reactive oxygen species (ROS) in mouse cells, and ROS in human cells. Importantly, mice treated with CLDC+MPF 3 days prior to challenge survived lethal intranasal infection with virulent F. tularensis. Similarly to in vitro observations, in vivo protection was dependent on the presence of RNS and ROS. Lastly, CLDC+MPF was also effective at controlling infections with Yersinia pestis, Burkholderia pseudomallei and Brucella abortus. Thus, CLDC+MPF represents a novel prophylaxis to protect against multiple, highly virulent pathogens.
Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, United States of America.
Robin
R
Ireland
Norma
N
Olivares-Zavaleta
Jonathan M
JM
Warawa
Frank C
FC
Gherardini
Clayton
C
Jarrett
B Joseph
BJ
Hinnebusch
John T
JT
Belisle
Jeffery
J
Fairman
Catharine M
CM
Bosio
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000942:Antigens, Bacterial / Q000494:pharmacology; D002003:Brucella abortus / Q000254:growth & development / Q000472:pathogenicity; D002006:Brucellosis / Q000188:drug therapy / Q000517:prevention & control; D016957:Burkholderia pseudomallei / Q000254:growth & development / Q000472:pathogenicity; D002412:Cations / Q000494:pharmacology; D002478:Cells, Cultured; D004247:DNA / Q000494:pharmacology*; D005604:Francisella tularensis / Q000254:growth & development* / Q000472:pathogenicity; D006801:Humans; D008081:Liposomes / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000382:microbiology; D008297:Male; D008554:Melioidosis / Q000188:drug therapy / Q000517:prevention & control; D000090204:Mesothelin; D051379:Mice; D008810:Mice, Inbred C57BL; D010930:Plague / Q000188:drug therapy / Q000517:prevention & control; D013047:Specific Pathogen-Free Organisms; D014406:Tularemia / Q000188:drug therapy / Q000517:prevention & control*; D014774:Virulence; D015010:Yersinia pestis / Q000254:growth & development / Q000472:pathogenicity
D000900:Anti-Bacterial Agents; D000942:Antigens, Bacterial; D002412:Cations; D008081:Liposomes; C000715528:Msln protein, mouse; D004247:DNA; D000090204:Mesothelin