Ignoring the "Itch": The Global Health Problem of Scabies.

Infestation with Sarcoptes scabiei var. hominis is a common human parasitic affliction endemic in tropical developing countries. Scabies is transmitted by close person-person contact, and outbreaks have been reported in reception centers for asylum seekers. Scabies presents clinically as extremely pruritic excoriated papules and linear burrows in the skin. This infestation predisposes to bacterial skin infections that can result in serious complications affecting the kidneys and possibly the heart. Treatment of individuals with scabies and their close contacts involves the use of antiparasitic agents. First-line treatment is topical 5% permethrin cream. Community mass drug administration, followed by active case finding with targeted treatment, is a promising approach that can reduce the prevalence of both scabies and bacterial skin infections. Organizations such as the International Alliance for the Control of Scabies are advocating for the development of integrated disease control strategies in an effort to decrease scabies infestation worldwide.

Syphilis: Re-emergence of an old foe.

Syphilis is caused by infection with Treponema pallidum subsp. pallidum, a not-yet-cultivable spiral-shaped bacterium that is usually transmitted by sexual contact with an infected partner or by an infected pregnant woman to her fetus. There is no vaccine to prevent syphilis. Diagnosis and treatment of infected individuals and their contacts is key to syphilis control programs that also include sex education and promotion of condom use to prevent infection. Untreated syphilis can progress through four stages: primary (chancre, regional lymphadenopathy), secondary (disseminated skin eruptions, generalized lymphadenopathy), latent (decreased re-occurrence of secondary stage manifestations, absence of symptoms), and tertiary (gummas, cardiovascular syphilis and late neurological symptoms). The primary and secondary stages are the most infectious. WHO estimates that each year 11 million new cases of syphilis occur globally among adults aged 15-49 years. Syphilis has re-emerged in several regions including North America, Western Europe, China and Australia. Host-associated factors that drive the re-emergence and spread of syphilis include high-risk sexual activity, migration and travel, and economic and social changes that limit access to health care. Early, uncomplicated syphilis is curable with a single intramuscular injection of benzathine penicillin G (BPG), the first line drug for all stages of syphilis. Emergence of macrolide-resistant T. pallidum has essentially precluded the empirical use of azithromycin as a second-line drug for treatment of syphilis. Virulence attributes of T. pallidum are poorly understood. Genomic and proteomic studies have provided some new information concerning how this spirochete may evade host defense mechanisms to persist for long periods in the host.

Pinta: Latin America's Forgotten Disease?

Pinta is a neglected, chronic skin disease that was first described in the sixteenth century in Mexico. The World Health Organization lists 15 countries in Latin America where pinta was previously endemic. However, the current prevalence of pinta is unknown due to the lack of surveillance data. The etiological agent of pinta, Treponema carateum, cannot be distinguished morphologically or serologically from the not-yet-cultivable Treponema pallidum subspecies that cause venereal syphilis, yaws, and bejel. Although genomic sequencing has enabled the development of molecular techniques to differentiate the T. pallidum subspecies, comparable information is not available for T. carateum. Because of the influx of migrants and refugees from Latin America, U.S. physicians should consider pinta in the differential diagnosis of skin diseases in children and adolescents who come from areas where pinta was previously endemic and have a positive reaction in serological tests for syphilis. All stages of pinta are treatable with a single intramuscular injection of penicillin.

Ebola Virus Disease: Rapid Diagnosis and Timely Case Reporting are Critical to the Early Response for Outbreak Control.

Ebola virus disease (EVD) is a life-threatening zoonosis caused by infection with the Ebola virus. Since the first reported EVD outbreak in the Democratic Republic of the Congo, several small outbreaks have been reported in central Africa with about 2,400 cases occurring between 1976 and 2013. The 2013-2015 EVD outbreak in west Africa is the first documented outbreak in this region and the largest ever with over 27,000 cases and more than 11,000 deaths. Although EVD transmission rates have recently decreased in west Africa, this crisis continues to threaten global health and security, particularly since infected travelers could spread EVD to other resource-limited areas of the world. Because vaccines and drugs are not yet licensed for EVD, outbreak control is dependent on the use of non-pharmaceutical interventions (e.g., infection control practices, isolation of EVD cases, contact tracing with follow-up and quarantine, sanitary burial, health education). However, delays in diagnosing and reporting EVD cases in less accessible rural areas continue to hamper control efforts. New advances in rapid diagnostics for identifying presumptive EVD cases and in mobile-based technologies for communicating critical health-related information should facilitate deployment of an early response to prevent the amplification of sporadic EVD cases into large-scale outbreaks.

Yaws: 110 years after Castellani's discovery of Treponema pallidum subspecies pertenue.

Yaws is a neglected infectious disease that affects mostly children and adolescents living in poor, rural communities in humid, tropical areas of Africa, southeast Asia, and the Pacific Islands. The etiological agent of yaws, Treponema pallidum subspecies pertenue (T. pertenue), was discovered by Aldo Castellani in 1905 shortly after Schaudinn and Hoffmann discovered the etiological agent of syphilis, T. pallidum subspecies pallidum. The discovery of T. pertenue enabled the development of animal models and the identification of an effective antibiotic treatment (i.e., penicillin) for yaws. A World Health Organization (WHO) mass treatment campaign from 1952 to 1964 reduced the global burden of yaws by 95%, but failed to eradicate this disease. Today, 110 years after Castellani's discovery of T. pertenue, yaws is again targeted for eradication. Recent advances in the treatment and diagnosis of yaws improve the likelihood of success this time. However, several challenges must be overcome to make the goal of yaws eradication attainable.

TLR2 and TLR4 mediate the TNFα response to Vibrio vulnificus biotype 1.

Vibrio vulnificus (Vv) is a pathogenic bacterium that can cause life-threatening infections in humans. Most fatal cases are due to septic shock that results from dysregulation of cytokines, particularly TNFα, which plays a critical role in the outcome of Vv infection. The goal of this study was to investigate the Toll-like receptor (TLR)-mediated TNFα response to four Vv biotype 1 strains using mice deficient for TLR2, TLR4, and TLR2/TLR4. Ex vivo assays were performed with blood, splenocytes, and Kupffer cells (KC) from wild-type (WT) and TLR-knockout (KO) mice using formalin-inactivated Vv (f-Vv) as stimulant. All f-Vv biotype 1 strains elicited strong TNFα production by WT mouse blood and cells, which was TLR2 and TLR4 dependent. OxPAPC, an inhibitor of TLR2 and TLR4 signaling, effectively blunted the TLR-mediated TNFα response to f-Vv. Furthermore, TLR2 KO and TLR2/TLR4 KO mice were more resistant to lethal infection with Vv ATCC 27562 than WT mice, perhaps due to attenuation of the TNFα response. These data suggest that it may be possible to devise strategies to specifically target the harmful TLR-mediated TNFα response as an adjunct to antibiotic treatment of severe Vv infection.

A synthetic lymph node containing inactivated Treponema pallidum cells elicits strong, antigen-specific humoral and cellular immune responses in mice.

The goal of this study was to investigate the use of a synthetic lymph node (SLN) for delivery of Treponema pallidum (Tp) antigens. Immune responses of C57BL/6 mice were analyzed at 4, 8, and 12 weeks after SLN implantation. Group 1 mice received SLN with no antigen; Group 2, SLN with formalin-inactivated Tp (f-Tp); and Group 3, SLN with f-Tp plus a CpG oligodeoxynucleotide. When tested by ELISA, sera from Group 2 and Group 3 mice showed stronger IgG antibody reactivity than sera from Group 1 mice to sonicates of f-Tp or untreated Tp, but not to sonicate of normal rabbit testicular extract at all times. The IgG1 level was higher than IgG2c level for Group 2 mice at all times and for Group 3 mice at 4 and 8 weeks. IgG1 and IgG2c levels were nearly equivalent for Group 3 mice at 12 weeks. Immunoblotting showed that IgG from Group 2 and Group 3 mice recognized several Tp proteins at all times. Supernatants of splenocytes from Group 2 and Group 3 mice contained significantly more IFNγ than those from Group 1 mice after stimulation with f-Tp at all times. A significant level of IL-4 was not detected in any supernatants. These data show that strong humoral and cellular immune responses to Tp can be elicited via a SLN.

Old foes, new challenges: syphilis, cholera and TB.

Syphilis, cholera and TB have re-emerged and now affect the health of countless humans globally. In this article, we review current information concerning the biology and epidemiology of these bacterial diseases with the goal of developing a better understanding of factors that have led to their resurgence and that threaten to compromise their control. The impact of microbial and environmental change notwithstanding, the main factors common to the re-emergence of syphilis, cholera and TB are human demographics and behavior. This information is critical to developing targeted strategies aimed at preventing and controlling these potentially deadly infectious diseases.

Role of TLR4 in the host response to Vibrio vulnificus, an emerging pathogen.

The incidence of infection with Vibrio vulnificus is increasing due to changing ecologic and demographic factors. Most fatal cases are caused by septic shock that results from dysregulation of proinflammatory cytokines such as tumor necrosis factor-alpha (TNFalpha), presumably due to interaction of V. vulnificus components with Toll-like receptors (TLRs). The goal of this study was to investigate the role of TLR4 in the host response to V. vulnificus. Results obtained using V. vulnificus type strain ATCC 27562 showed that (1) TLR4 signaling is myeloid differentiation factor 88 dependent and plays a key role in TNFalpha production by mouse blood and splenocytes stimulated ex vivo with inactivated V. vulnificus cells, (2) TLR4 signaling is deleterious in a mouse model of V. vulnificus infection, (3) signaling by TLR(s), exclusive of TLR4, is needed to eradicate infection, and (4) the TLR-mediated TNFalpha response plays a critical role in determining the outcome of infection. These results suggest that blockade of the harmful TLR4-mediated inflammatory response could be a useful adjunct to antibiotics for treatment of severe V. vulnificus infection.