Biological weapons

Pappas, Georgios; Panagopoulou, Paraskevi; Christou, Leonidas; Akritidis, Nikolaos

doi:10.1007/s00018-006-6311-4

Cited by 218 publications

(102 citation statements)

References 46 publications

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“…Although the means of disease transmission is well delineated (3), in certain cases the pathogen's entry into the human body cannot be clearly defi ned; this has led to suggestions of direct human-to-human transmission and also to the increasing recognition of airborne brucellosis, which is important in the context of the role of Brucella spp. as potential biological weapons (4). Another understudied transmission route is entry by direct contact through skin and mucosal abrasions.…”

Section: Brucellosis In Infant After Familial Outbreakmentioning

confidence: 99%

Brucellosis in Infant after Familial Outbreak

Makis

Pappas

Galanakis

et al. 2008

Emerg. Infect. Dis.

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Section: Brucellosis In Infant After Familial Outbreakmentioning

confidence: 99%

Brucellosis in Infant after Familial Outbreak

Makis

Pappas

Galanakis

et al. 2008

Emerg. Infect. Dis.

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“…Brucella melitensis is the predominant cause of human brucellosis; however, B. abortus, B. suis, and B. canis can also infect humans (4). Human brucellosis is typically acquired by consuming contaminated milk products or via inhalation of aerosolized bacteria from occupational hazards (5). Human brucellosis is a debilitating disease in which most people initially experience a period of undulating fever which can progress to a chronic infection if untreated or if antibiotic treatment fails.…”

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confidence: 99%

The Bacterial Second Messenger Cyclic di-GMP Regulates Brucella Pathogenesis and Leads to Altered Host Immune Response

et al. 2016

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f Brucella species are facultative intracellular bacteria that cause brucellosis, a chronic debilitating disease significantly impacting global health and prosperity. Much remains to be learned about how Brucella spp. succeed in sabotaging immune host cells and how Brucella spp. respond to environmental challenges. Multiple types of bacteria employ the prokaryotic second messenger cyclic di-GMP (c-di-GMP) to coordinate responses to shifting environments. To determine the role of c-di-GMP in Brucella physiology and in shaping host-Brucella interactions, we utilized c-di-GMP regulatory enzyme deletion mutants. Our results show that a ⌬bpdA phosphodiesterase mutant producing excess c-di-GMP displays marked attenuation in vitro and in vivo during later infections. Although c-di-GMP is known to stimulate the innate sensor STING, surprisingly, the ⌬bpdA mutant induced a weaker host immune response than did wild-type Brucella or the low-c-di-GMP guanylate cyclase ⌬cgsB mutant. Proteomics analysis revealed that c-di-GMP regulates several processes critical for virulence, including cell wall and biofilm formation, nutrient acquisition, and the type IV secretion system. Finally, ⌬bpdA mutants exhibited altered morphology and were hypersensitive to nutrient-limiting conditions. In summary, our results indicate a vital role for c-di-GMP in allowing Brucella to successfully navigate stressful and shifting environments to establish intracellular infection. Brucella species are Gram-negative, facultative intracellular bacterial pathogens that cause brucellosis, the most prevalent zoonosis worldwide (1, 2). With more than 500,000 infections per year, the high incidence of brucellosis in southeastern Europe, the Mediterranean, South America, and Africa causes a major economic burden (2, 3). In animals, brucellosis is characterized by increased abortion, weak offspring, and decreased milk production. Brucella melitensis is the predominant cause of human brucellosis; however, B. abortus, B. suis, and B. canis can also infect humans (4). Human brucellosis is typically acquired by consuming contaminated milk products or via inhalation of aerosolized bacteria from occupational hazards (5). Human brucellosis is a debilitating disease in which most people initially experience a period of undulating fever which can progress to a chronic infection if untreated or if antibiotic treatment fails. Complications of chronic infections include liver damage, orchitis, endocarditis, and arthritis (1, 4).Brucella spp. have the ability to infect both professional and nonprofessional phagocytes (6). Because of this, Brucella spp. encounter varied environments both throughout the body and within a cell and must adapt accordingly. To date, few virulence factors have been identified in Brucella, and even less is known about how these virulence factors are regulated. Subsequently, little is known how Brucella adapts to its rapidly changing environments and how it alternates between acute and chronic virulence.The second messenger cyclic di-GMP (c-di-GMP...

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“…The infection can be transmitted to humans by several ways, among which inhalation of infected aerosols is one of the most frequent. The easy aerosolization and airborne transmission of Brucella species has contributed to their consideration as potential biological weapons (1) and their classification by the CDC and NIAID as category B bioterrorism agents. Outbreaks of human brucellosis due to airborne transmission have been reported in different settings, including abattoirs, vaccine production laboratories, and rural areas (3)(4)(5).…”

mentioning

confidence: 99%

Key Role of Toll-Like Receptor 2 in the Inflammatory Response and Major Histocompatibility Complex Class II Downregulation in Brucella abortus-Infected Alveolar Macrophages

et al. 2014

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c Alveolar macrophages (AM) seem to constitute the main cellular target of inhaled brucellae. Here, we show that Brucella abortus invades and replicates in murine AM without inducing cytotoxicity. B. abortus infection induced a statistically significant increase of tumor necrosis factor alpha (TNF-␣), CXCL1 or keratinocyte chemoattractant (KC), interleukin-1␤ (IL-1␤), IL-6, and IL-12 in AM from C57BL/6 mice and BALB/c mice, but these responses were generally weaker and/or delayed compared to those elicited in peritoneal macrophages. Studies using knockout mice for TLR2, TLR4, and TLR9 revealed that TNF-␣ and KC responses were mediated by TLR2 recognition. Brucella infection reduced in a multiplicity of infection-dependent manner the expression of major histocompatibility complex class II (MHC-II) molecules induced by gamma interferon (IFN-␥) in AM. The same phenomenon was induced by incubation with heat-killed B. abortus (HKBA) or the lipidated form of the 19-kDa outer membrane protein of Brucella (L-Omp19), and it was shown to be mediated by TLR2 recognition. In contrast, no significant downregulation of MHC-II was induced by either unlipidated Omp19 or Brucella LPS. In a functional assay, treatment of AM with either L-Omp19 or HKBA reduced the MHC-II-restricted presentation of OVA peptides to specific T cells. One week after intratracheal infection, viable B. abortus was detected in AM from both wild-type and TLR2 KO mice, but CFU counts were higher in the latter. These results suggest that B. abortus survives in AM after inhalatory infection in spite of a certain degree of immune control exerted by the TLR2-mediated inflammatory response. Both the modest nature of the latter and the modulation of MHC-II expression by the bacterium may contribute to such survival. Brucellosis is zoonotic disease caused by Brucella species, which is distributed worldwide and affects over 500,000 people annually (1) and for which there is no approved efficacious human vaccine available. Brucella melitensis, B. suis, and B. abortus are the most pathogenic species for humans and are responsible for the vast majority of human cases (2). The infection can be transmitted to humans by several ways, among which inhalation of infected aerosols is one of the most frequent. The easy aerosolization and airborne transmission of Brucella species has contributed to their consideration as potential biological weapons (1) and their classification by the CDC and NIAID as category B bioterrorism agents. Outbreaks of human brucellosis due to airborne transmission have been reported in different settings, including abattoirs, vaccine production laboratories, and rural areas (3-5). Notably, aerosols have been implicated in most cases of laboratory-acquired brucellosis, which is considered the commonest laboratory-acquired infection (6).Lung epithelial cells and alveolar macrophages (AM) are the first cells to be contacted by inhaled microorganisms. AM constitute the first line of pulmonary defense and are capable of initiating a local immune respons...

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Biological weapons

Cited by 218 publications

References 46 publications

Brucellosis in Infant after Familial Outbreak

Brucellosis in Infant after Familial Outbreak

The Bacterial Second Messenger Cyclic di-GMP Regulates Brucella Pathogenesis and Leads to Altered Host Immune Response

Key Role of Toll-Like Receptor 2 in the Inflammatory Response and Major Histocompatibility Complex Class II Downregulation in Brucella abortus-Infected Alveolar Macrophages

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