Anu Kantele

Antimicrobials Increase Travelers' Risk of Colonization by Extended-Spectrum Betalactamase-Producing Enterobacteriaceae

Colonized travelers contribute to the pandemic spread of resistant intestinal bacteria. This study is the first to show that antimicrobial use during travel predisposes to colonization by intestinal extended-spectrum beta-lactamase-producing Enterobacteriaceae. Travelers refrain from taking unnecessary antibiotics.

Review of cases with the emerging fifth human malaria parasite, Plasmodium knowlesi.

Human malaria has been known to be caused by 4 Plasmodium species, with Plasmodium falciparum causing the most-severe disease. Recently, numerous reports have described human malaria caused by a fifth Plasmodium species, Plasmodium knowlesi, which usually infects macaque monkeys. Hundreds of human cases have been reported from Malaysia, several cases have been reported in other Southeast Asian countries, and a few cases have been reported in travelers visiting these areas. Similarly to P. falciparum, P. knowlesi can cause severe and even fatal cases of disease that are more severe than those caused by the other Plasmodium species. Polymerase chain reaction is of value for diagnosis because P. knowlesi infection is easily misdiagnosed as less dangerous Plasmodium malariae infection with conventional microscopy. P. knowlesi infection should be suspected in patients who are infected with malaria in Southeast Asia. If human-mosquito-human transmission were to occur, the disease could spread to new areas where the mosquito vectors live, such as the popular tourist areas in western India.

Monkey Malaria in a European Traveler Returning from Malaysia

In 2007, a Finnish traveler was infected in Peninsular Malaysia with Plasmodium knowlesi, a parasite that usually causes malaria in monkeys. P. knowlesi has established itself as the fifth Plasmodium species that can cause human malaria. The disease is potentially life-threatening in humans; clinicians and laboratory personnel should become more aware of this pathogen in travelers.

Active immunity is seen as a reduction in the cell response to oral live vaccine.

Oral immunization elicits a response of antibody-secreting cells (ASC) in the peripheral blood; these cells are believed to originate in the mucosa and hence give information on the mucosal immune response. We have shown earlier that oral booster immunization is followed by an elevated ASC response reflecting an immunologic memory. In the present study we show that a booster dose of a live bacterial vaccine given at a time of active mucosal immunity elicits a low ASC response only. This is probably because the multiplication of the live vaccine is inhibited in the gut, resulting in a low actual dose of the antigen. This situation may be an example of the protective immunity manifested when an orally immunized person encounters the pathogen in nature, and could be used to assess the protective immunity.

Homing potentials of circulating antibody-secreting cells after administration of oral or parenteral protein or polysaccharide vaccine in humans

The site of antigen encounter influences the Ig-distribution and homing potentials of circulating antibody-secreting cells (ASC) induced. After oral antigen administration, the majority ASC secrete the mucosal Ig-isotype, IgA, and all of them express the gut homing receptor (HR), alpha 4 beta 7, thus implying mucosal homing of these cells. Parenteral protein vaccine induces an IgG-dominated response with a low proportion of alpha 4 beta 7 expressing cells. However, a polysaccharide vaccine, even if administered parenterally, elicits an IgA-dominated response, hence suggesting homing to the mucosa. In order to study the influence of the nature of the antigen on the targeting of the ASC response, the present work compares the homing potentials of circulating ASC in humans after administration of an oral Salmonella Typhi Ty21a vaccine (antigen studied: O-9,12 polysaccharide), an oral recombinant cholera vaccine (antigen studied: cholera toxin B-subunit, CTB protein), a parenteral pneumococcal vaccine (antigen studied: Pnc capsular polysaccharide 19F) or a parenteral tetanus toxoid vaccine (antigen studied: TT protein). alpha 4 beta 7 was expressed on a higher proportion of ASC induced by oral O-9,12 (99%) and CTB (99%) than by parenteral Pnc (70%) or TT (63%). L-selectin, the peripheral lymph node HR, was expressed on a smaller proportion of ASC induced by O-9,12 (37%) or CTB (43%) than of those induced by Pnc (78%) or TT (81%). The results imply that even if the nature of the antigen has a profound effect on the Ig-distribution of the ASC response, it does not seem to influence the targeting of the response.

Obatoclax, saliphenylhalamide and gemcitabine inhibit influenza A virus infection

Background: Novel options should be developed for treatment of IAV infections. Results: Obatoclax, saliphenylhalamide, and gemcitabine target host factors and inhibit IAV and several other viruses infections. Conclusion: These compounds represent potent antiviral agents. Significance: These compounds could be exploited in treatment of severe viral infections. Influenza A viruses (IAVs) infect humans and cause significant morbidity and mortality. Different treatment options have been developed; however, these were insufficient during recent IAV outbreaks. Here, we conducted a targeted chemical screen in human nonmalignant cells to validate known and search for novel host-directed antivirals. The screen validated saliphenylhalamide (SaliPhe) and identified two novel anti-IAV agents, obatoclax and gemcitabine. Further experiments demonstrated that Mcl-1 (target of obatoclax) provides a novel host target for IAV treatment. Moreover, we showed that obatoclax and SaliPhe inhibited IAV uptake and gemcitabine suppressed viral RNA transcription and replication. These compounds possess broad spectrum antiviral activity, although their antiviral efficacies were virus-, cell type-, and species-specific. Altogether, our results suggest that phase II obatoclax, investigational SaliPhe, and FDA/EMEA-approved gemcitabine represent potent antiviral agents.

Cross-reactive gut-directed immune response against Salmonella enterica serovar Paratyphi A and B in typhoid fever and after oral Ty21a typhoid vaccination.

BACKGROUND There are no vaccines against paratyphoid fever in clinical use. The disease has become more wide-spread and there is a growing problem of antibiotic resistance among the strains. Previous reports suggest that the oral live Salmonella Typhi Ty21a-vaccine confers protection against paratyphoid B fever. Data on efficacy against paratyphoid A fever are somewhat contentious. The present study investigated the immunological basis for such efficacy reports at a single-cell level: plasmablasts (identified as antibody-secreting cells, ASC) were studied for secretion of antibodies cross-reactive with Salmonella Paratyphi in the circulation of patients with enteric fever and of volunteers vaccinated with Ty21a. MATERIALS AND METHODS Thirty volunteers immunized with Ty21a and five patients with enteric fever were investigated for Salmonella Typhi and Salmonella Paratyphi A/B/C-specific circulating plasmablasts. PBMC were sorted by their expression of homing receptors (HR) for the intestine (α4β7), peripheral lymph node (l-selectin) and skin (CLA) and typhoid- and paratyphoid-specific plasmablasts were enumerated with ELISPOT. RESULTS Before vaccination, no cross-reactive ASC were found in the volunteers. In addition to the Salmonella Typhi-specific response, a significant cross-reactive immune response was mounted against Salmonella Paratyphi A and B both in the patients and the vaccinees. The magnitude of the response increased in the order Salmonella Paratyphi A (median 30 ASC/10(6) PBMC)→Salmonella Paratyphi B (median 81)→Salmonella Typhi (median 301) in the vaccinees. Both in patients and in vaccinees, the homing receptor (HR) selection favored homing to the gut, indicating a humoral intestinal immune response. CONCLUSIONS These immunological data provide evidence consistent with previous reports describing certain levels of cross-protective efficacy of Ty21a against paratyphoid fever. Controlled studies are needed to evaluate cross-protective efficacy. In the current situation where paratyphoid fever is emerging and no vaccines are available, any level of cross-protective capacity is valuable.

Serodiagnosis of Primary Infections with Human Parvovirus 4, Finland

To determine the prevalence of parvovirus 4 infection and its clinical and sociodemographic correlations in Finland, we used virus-like particle–based serodiagnostic procedures (immunoglobulin [Ig] G, IgM, and IgG avidity) and PCR. We found 2 persons with parvovirus 4 primary infection who had mild or asymptomatic clinical features among hepatitis C virus–infected injection drug users.

Expression of Homing Receptors on IgA1 and IgA2 Plasmablasts in Blood Reflects Differential Distribution of IgA1 and IgA2 in Various Body Fluids

ABSTRACT Although secretory IgA is the most abundantly produced Ig isotype, the mechanisms underlying the differential distribution of IgA subclasses in various body fluids remain unclear. To explore these mechanisms, we examined the distribution of IgA subclasses, the influence of the nature and sites of encounters with antigens, and the correlation between IgA subclass distribution and homing potentials of circulating IgA plasmablasts. IgA1 predominated in serum, tears, nasal wash fluid, and saliva; the levels of IgA1 and IgA2 were comparable in vaginal wash fluid; and IgA2 predominated in intestinal lavage fluids. Seventy-one percent of circulating IgA plasmablasts secreted IgA1. The intestinal homing receptor (HR), α4β7, was expressed more frequently on IgA2 than on IgA1 plasmablasts, with no differences in the expression of other HRs. IgA subclass distribution among circulating antigen-specific antibody-secreting cells (ASC) was dependent on the nature of the antigen: following vaccination with Salmonella enterica serovar Typhi, unconjugated pneumococcal polysaccharide, or Haemophilus influenzae polysaccharide-diphtheria toxoid conjugate, the proportions of specific IgA1 ASC were 74%, 47%, 56%, and 80%, respectively. HR expression depended on the route of administration: expression of HRs was different after oral than after parenteral vaccination, while no difference was seen between HR expression of antigen-specific IgA1 and IgA2 ASC induced via the same route. The key factors determining IgA subclass distribution in a given secretion are the nature of the antigens encountered at a particular site and the site-specific homing instructions given to lymphocytes at that site. These two factors are reflected as differences in the homing profiles of the total populations of circulating IgA1 and IgA2 plasmablasts.

Peripheral blood antibody-secreting cells in the evaluation of the immune response to an oral vaccine.

Specific antibody-secreting cells (ASC) appear in the blood as a response to oral vaccination in humans. Based on information from animal experiments, these cells are believed to be migrating to the mucosa. This review summarizes a series of studies aimed at a detailed characterization of the ASC response to a prototype oral vaccine Salmonella typhi Ty21a, with respect to its kinetics, Ig-class distribution, antigen specificity, influence of the administration route and nature of the antigen, and the corresponding antibody responses in serum. Different vaccine formulations as well as dosage schedules are compared, and the response to booster immunization is described. The response manifested by ASC in blood is shown to be independent from serum antibody responses. Moreover, it is shown to parallel with the results obtained for protection in field trials. Finally, some data on the homing receptor expression of these cells are presented, giving further evidence for the mucosal homing of these cells. The ASC assay offers a practical means for assessing immune response to oral vaccines in humans. It can be used as a laboratory parameter correlated with protection conferred by an oral typhoid vaccine. It can even be applied to measure active mucosal immunity, i.e., protective immunity by showing the relative reduction of the ASC response to an oral dose of live vaccine.