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Legionella pneumonia is a fatal disease caused by Legionella pneumophila, a bacterium belonging to the genus Legionella. The incidence of this disease has been increasing since 2005 and has continued to increase following the COVID-19 pandemic in Japan. Furthermore, Legionella pneumonia mortality rates have increased slightly since the pandemic due to some plausible reasons. The increased proportion of older patients with legionellosis might affect it because advanced age is a major risk factor for disease mortality. Additionally, physicians were focused on COVID-19 while examining febrile patients; therefore, they might have missed the early diagnosis of other respiratory infections, including Legionella pneumonia., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Introduction: Bacterial culture remains the gold standard for the diagnosis of legionellosis. However, past reports indicate that most physicians use the urinary antigen test (UAT) alone. Combining it with other tests is important, especially in patients with negative UAT results. The aim of this study was to investigate the current situation of legionellosis diagnostics and clarify the issues that need to be addressed., Methods: Between March 1, 2021 and April 30, 2021, a questionnaire survey was conducted in an anonymous manner among physicians working in Japan. Questionnaires were generated on a website and asked questions in a multiple-choice format., Results: Valid responses were received from 309 physicians during the study period. Most (92.9%) physicians reported using UAT as the initial test for patients suspected of having legionellosis, and <10% reported using other tests (e.g., culture, nucleic acid amplification test [NAAT], Gimenez staining, and serum antibody titer measurement [ATM]). When the initial test result was negative, 63% of physicians reported not conducting additional tests. Even when they chose to run additional tests, at most 27.8%, 23.6%, 12.3%, and 10.4% of all physicians used NAAT, culture, Gimenez staining, and serum ATM, respectively. The major reasons for not using tests other than UAT were "unavailability in the medical facility," "long turn-around time," and "difficult to collect sputum.", Conclusions: The present survey revealed that most physicians in Japan used UAT alone for diagnosing legionellosis. Eliminating barriers to creating a reasonable environment and edification of physicians are needed to improve the current situation., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Although rapid antigen tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is convenient, some articles have demonstrated their low sensitivity indicating false-negative results should always be considered. Here, we raise the issue of false-positive on rapid antigen tests for SARS-CoV-2 with the first case of acute HIV infection who repeatedly positive for the rapid antigen test. A 39-year-old man was admitted to our hospital complaining of high-grade fever, dry cough, general fatigue, and anorexia. The rapid antigen test performed on a nasopharyngeal swab sample was positive, therefore the patient was separated in an isolated room apart from the COVID-19 ward while awaiting the confirmatory RT-PCR result. However, the RT-PCR for SARS-CoV-2 performed on nasopharyngeal swabs was repeatedly negative (three times), while the antigen test was repeatedly positive (three times in total). This patient was eventually diagnosed with acute human immunodeficiency virus (HIV) infection based on a high titer of HIV-RNA and absence of plasma HIV-1/2 antibodies. Physicians should consider the possibility of false-positive results in addition to false-negative results when using a rapid antigen test for SARS-CoV-2, and keep in mind that nucleic acid amplification tests are needed to confirm the diagnosis., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Since the Okinawan islands are located in the southernmost part of Japan, where the climate is subtropical, several episodes of influenza epidemics occur during the summer season. More recently, we have demonstrated that summer influenza epidemics occur every year. After the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in January 2020, measures to avoid disease transmission have been widely promoted in Japan, such as the use of masks, handwashing, remote work, and cancellation of large events. These measures might also have reduced the spread of other infectious diseases, such as the seasonal influenza. Based on this background, we evaluated weekly influenza activity in the 2019/2020 season. After the SARS-CoV-2 pandemic, the summer influenza in the Okinawa prefecture disappeared in 2020. The reasons for the disappearance of summer influenza in Okinawa are discussed herein., Competing Interests: Conflict of Interest The authors have no conflicts of interest to declare., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Molecular diagnostic methods have recently gained widespread use, and consequently, the importance of viral pathogens in community-acquired pneumonia (CAP) has undergone re-evaluation. Under these circumstances, the role of Chlamydophila pneumoniae as a pathogen that causes CAP also needs to be reviewed., Methods: We reviewed articles that contained data on the frequency of identification of C. pneumoniae pneumonia as a causative pathogen for CAP. The articles were identified by performing a search in PubMed with the keywords "community-acquired pneumonia" and "pathogen"., Results: Sixty-three articles were identified. The reviewed articles demonstrated that the rates of identification of C. pneumoniae as the causative pathogen for CAP were significantly lower in assessments based on polymerase chain reaction (PCR) methods than in those based on serological methods. In some studies, it was possible to compare both serological and PCR methods directly using the same set of samples., Conclusions: The use of PCR methods, including multiplex PCR assays, has revealed that C. pneumoniae may play a limited role as a pathogen for CAP., Competing Interests: Conflict of Interest The authors have no conflicts of interest., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Drug-induced pneumonitis is a disease encountered by pulmonologists in the clinical setting. The diagnosis generally considers the patient's clinical course and the results of peripheral blood tests, radiological examinations, and often bronchoscopic examinations. However, few studies have reported the association between radiological patterns such as ground-glass opacity (GGO) or consolidation, and bronchoalveolar lavage fluid (BALF) cell fractions. This study aimed to clarify this association., Methods: Patients with a Naranjo's score of probable or definite were enrolled, and all 30 patients were categorized under probable. Data such as patient background, blood examination results, radiological findings, and BALF cell fractions were retrospectively collected. The association between BALF cell fractions and other factors such as chest computed tomography (CT) findings was evaluated., Results: The most common radiological finding in patients with lymphocyte-dominant BALF was GGO, with only one patient exhibiting consolidation. However, patients with eosinophil-dominant BALF were more likely to have consolidation; only three cases showed crazy paving and one showed GGO. In addition, patients with a GGO-dominant pattern on CT had an increased lymphocyte fraction of 41.0%; those with a consolidation-dominant pattern showed a relatively high eosinophil fraction of 5.2%; and those with a crazy paving pattern showed elevated eosinophil and neutrophil fractions of 19.1% and 9.9%, respectively., Conclusions: In this study, a remarkable difference in radiological findings was observed among different BALF patterns., Competing Interests: Declaration of Competing Interest None of the authors has any conflict of interest to report., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

This prospective study was performed to evaluate and compare the performance of the multiplex PCR Seeplex ® assays and Anyplex™ II assays. From May 2014 until April 2016, a total of 247 respiratory samples were collected in Okinawa, Japan. Multiple respiratory pathogens were detected in 37% of patients with positive results. The most prevalent pathogens were influenza A virus and respiratory syncytial virus B. Despite minor differences in capabilities, both the Seeplex ® assays and Anyplex™ II assays can be easily implemented in diagnostic or research laboratories to optimize the detection and management of respiratory pathogen induced diseases., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Etiological epidemiology and diagnosis are important issues for CAP and NHCAP. Despite the availability of effective therapies, significant morbidity and mortality ensues., Methods: We retrospectively analyzed the etiology of 200 pneumonia patients at the University of the Ryukyus Hospital. Patients were categorized into CAP (n = 97) or NHCAP (n = 103), according to the Japanese Respiratory Society guidelines. Diagnoses were made using clinical tests including, Gram stain, bacterial culture, serum and urinary tests., Results: Pathogens were detected in 71% of patients, and identified as the source of infection in 52% (104/200). The majority of patients suffered from Streptococcus pneumoniae (32/200), Haemophilus influenzae (22/200), and Moraxella catarrhalis (16/200). Gram stain guided pathogen-oriented therapy decisions for 38 of 96 patients with unknown pathogens. Atypical pathogens were only diagnosed in CAP patients (n = 5). Severity of pneumonia was related to male sex (p = 0.006), and preexisting conditions, such as chronic heart failure (p < 0.001) and COPD (p < 0.001). Risk factors associated with increased length of stay included chronic heart failure, chronic renal failure, other pulmonary diseases and diabetes. Mortality for NHCAP patients was associated with lung cancer and bronchiectasis. CAP patients were more frequently admitted during winter months, while NHCAP patients were admitted during all other seasons. Seasonal patterns for individual pathogens could not be determined., Conclusion: Gram staining remains useful to guiding diagnostics. Pathogens affecting CAP and NHCAP patients were not significantly different; as such, attention should be focused on the management of underlying conditions. Clinical outcomes were not affected by guideline discordant therapy., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Here we report six cases of daptomycin (DAP)-induced eosinophilic pneumonia (DIEP) encountered at two medical centers and present a review of 43 DIEP patients from 26 studies to compare the clinical characteristics and radiographic findings of acute and chronic eosinophilic pneumonia (AEP; CEP). Four of the six patients did not exhibit respiratory symptoms, and one patient with only fever was misdiagnosed with DAP-induced fever. According to our literature review and the present findings, male sex and old age were dominant risk factors for DIEP. Fever and fine crackles were the most common clinical manifestations. The DAP dose and duration of administration were not significant risk factors for DIEP, and we also could not find any association between allergic predisposition and DIEP. Among the reviewed patients, 51.8% did not show more than 25% eosinophils in bronchoalveolar lavage, which is a criterion for the diagnosis of drug-induced eosinophilic pneumonia. Chest images of all patients showed CEP patterns such as multiple reticulonodular infiltrates in the subpleural region and diffuse bilateral pulmonary infiltrates with ground-glass opacities. However, 66.7% of patients also exhibited pleural effusion, a feature specific to AEP. All patients showed prompt recovery after DAP withdrawal. Our results suggest that clinicians should consider DIEP as a differential diagnosis when patients receiving DAP therapy, particularly men and elderly patients, present with fever, even in the absence of respiratory symptoms. Furthermore, they should be aware that the occurrence of DIEP is independent of the DAP dose and administration duration, and allergic reaction., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Neisseria meningitidis often causes meningitis and meningococcemia; however, meningococcal pneumonia is quite rare. Herein, we report a case of non-invasive meningococcal pneumonia initially misdiagnosed as pneumonia due to Moraxella catarrhalis on the basis of a Gram stain in a 43-year-old woman with asthma, type 2 diabetes mellitus, and schizophrenia. She visited our hospital following a 3-day history of fever, productive cough, and shortness of breath. Since her sputum smear revealed Gram-negative diplococcus and the chest radiograph showed infiltration in the lower right lung field, her initial diagnosis was pneumonia caused by M. catarrhalis. However, the next day, the sputum culture colonies were unlike those of M. catarrhalis, and matrix-assisted laser desorption/ionization time of flight mass spectrometry analysis revealed the pathogen to be N. meningitidis. As a result, we administered the appropriate treatment and ensured adequate infection prevention and control measures including, droplet precautions and prophylaxis provided to close contacts. Secondary infection did not occur. Although meningococcal pneumonia is not common, physicians should consider N. meningitidis when Gram-negative diplococci are observed in respiratory specimens, as N. meningitidis cannot be distinguished from M. catarrhalis with Gram staining alone. Moreover, it is also important to monitor the appearance of the pathogenic colonies and to closely coordinate with laboratory technicians to determine appropriate treatments. In this article, we review the previous case reports of meningococcal pneumonia reported in 1984-2015 in Japan, summarizing the clinical characteristics and comparing previous reviews of the literature., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background and Objective: In recent years, Streptococcus anginosus group (SAG) bacteria are becoming increasingly recognized as important pneumonia-causing pathogens. Although several small studies have been reported, the features of SAG pneumonia remain unclear, because the identification of SAG from sputum cultures is not routinely performed in most microbiology laboratories. The aim of this study was to elucidate the clinical characteristics of SAG pneumonia., Patient and Methods: This was a retrospective case-control study utilizing data obtained in our hospital between September 2009 and June 2016. We investigated 31 patients with SAG pneumonia (PWP), and also assessed the difference between the 31 PWP and 37 patients without pneumonia (PWOP) in whose sputum SAG was detected., Results: Seventy-one percent of the patients were men and the median age was 78 years in the PWP. Univariate analysis indicated that the PWP were significantly more often a bed-ridden (p < 0.01) with comorbid aspiration than were the PWOP (p < 0.05). Among the PWP, nursing and healthcare-associated pneumonia (NHCAP) was the more common type of pneumonia (54.8%). S. anginosus was detected significantly more frequently in sputum cultures of PWP than PWOP (p < 0.01), and multiple pathogens were detected more frequently in PWP (p < 0.01). Streptococcus constellatus was the most frequently detected pathogen in patients with a single bacterial infection. Empyema was observed only in patients with multiple bacteria., Conclusions: SAG should be recognized as important causative pathogens of pneumonia, particularly among elderly patients with underlying disease associated with aspiration. NHCAP was the more common type of SAG pneumonia in this study., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Among the Citrobacter genus, the most commonly isolated bacteria from human specimens are Citrobacter freundii and Citrobacter koseri, and previous cases of infection due to Citrobacter braakii have been rarely reported. We present a case of bacteremia due to C. braakii in a 38-year-old woman with cervical cancer. She was admitted to our hospital with complaints of a fever, chills, and nausea. Blood culture results showed gram-negative bacilli identified as C. braakii via matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis, although biochemical testing findings were suggestive of C. freundii. Since a rare pathogen was detected in the present case and the results of additional biochemical studies were suggestive of both C. braakii and Citrobacter farmeri, genetic analysis was conducted. Finally, the gram-negative bacilli were confirmed as C. braakii, a member of the C. freundii complex since 1993, by 16S ribosomal RNA gene sequencing analysis. The gastrointestinal tract was considered the portal of entry, because the patient had a rectal fistula and other cultures such as urine and vaginal discharge incubated species other than C. braakii. The patient recovered after receiving treatment with ciprofloxacin for 14 days. The epidemiology and clinical characteristics of C. braakii infection are still unknown because of the limitations in accurate identification by using currently available commercial biochemical testing and previously, only 6 cases of C. braakii infection have been reported. Physicians should focus on this species, because it causes community-acquired infections, although further studies are needed to clarify the clinical characteristics of C. braakii infections., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Previously, Veillonella species had been considered as nonpathogenic and rarely caused serious infections. We report a case of 25-year-old man with osteomyelitis caused by Veillonella species. He was admitted to the hospital due to an open fracture to the left radial bone caused by industrial washing machine accident, and emergency surgery was performed. However, wound infections occurred one week after the operation. Although Acinetobacter baumannii and Serratia marcescens were cultured from the pus, obligate anaerobic bacteria were not detected at that point. Debridement was repeated and antibiotics were changed according to the result of bacterial culture and drug sensitivity. Despite this, the infection was poorly controlled. On the 5th debridement, granulomatous bone tissues on pseudarthrosis were found for the first time at the infection site. Although no bacteria was detected with aerobic culture, anaerobic incubation revealed Gram-negative cocci which was later identified as Veillonella species by 16S rRNA gene sequence analysis. His condition improved without any additional debridement after adding effective antibiotics against Veillonella species. It is well known that prolonged infection with aerobes consumes oxygen in the infection site and leads the environment to more favorable conditions for anaerobic bacteria, thus we speculated that prolonged infection with bacteria such as S. marcescens induced the favorable environment for Veillonella species. Physicians should realize the importance of anaerobic culture method in routine practice, especially in complicated cases such as the present case. In this article, we reviewed case reports of Veillonella infection and summarized the clinical features of this organism., (Copyright © 2016. Published by Elsevier Ltd.)

We report a case of fatal pneumonia and viremia due to human parainfluenza virus type 1 (HPIV-1) in a 65-year-old male patient with adult T-cell leukemia-lymphoma (ATL) treated with mogamulizumab, a brand-new therapeutic agent for ATL. To our knowledge, this is the first report describing viremia due to HPIV-1. After administering mogamulizumab, lymphocyte count in the blood was drastically decreased and the patient suffered from complicated infections including gram-negative bacterial sepsis, cytomegalovirus antigenemia and aspergillosis. Although these infections were successfully controlled by broad spectrum antimicrobial therapy, patchy ground-grass opacities in the both lungs were gradually worsened. He finally died due to acute respiratory failure. Since findings of the chest CT was consistent with typical patterns of viral pneumonia, we screened major respiratory viruses in the peripheral blood with multiplex PCR, and it turned out that RNA of HPIV-1 was positive. Although ATL cells were not detected in the autopsied lungs and a variety of other tissues, cytoplasmic inclusion bodies, which are commonly observed in RNA viral infection, were abundantly observed in the autopsied lung tissue. These findings suggest that mogamulizumab accomplished complete remission of ATL, while the chemotherapy-induced prolonged lymphopenia caused fatal pneumonia and viremia due to HPIV-1. As it has been well recognized that community respiratory viruses including HPIV-1 often cause fatal pneumonia in patients with leukemia, but also there is no specific treatment for HPIV-1, we have to enforce standard precautions especially when we treat leukemic patients with intensively immunosuppressive agents such as mogamulizumab., (Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

High mobility group box 1 (HMGB-1) protein is involved in acute lung injury due to various etiologies. We evaluated HMGB-1 levels in sera and bronchoalveolar fluids in patients with pneumonia caused by Legionella pneumophila. Levels of HMGB-1 in the sera of patients with L. pneumophila pneumonia (32 cases) and control subjects (24 cases) were determined. Serum HMGB-1 levels in Legionella pneumonia were similar to those of the control subjects. No significant correlation between HMGB-1 levels and other biomarkers and the outcome of cases was observed. In contrast, HMGB-1 levels, as well as interferon-γ, in bronchoalveolar (BA) fluids from severe L. pneumophila pneumonia (7 cases) were significantly higher than those in the sera of identical patients. HMGB-1 levels in BA fluids were relatively higher in pneumonia cases with ALI than those without ALI. Our findings suggest that intra-pulmonary HMGB-1 may be involved in the pathophysiology of pneumonia caused by L. pneumophila., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

A 77-year-old man was admitted to our hospital complaining of general fatigue. Serum sodium was 116 mEq/l and serum antidiuretic hormone (ADH) was elevated. Radiologic examination revealed nodules in the brain as well as in both adrenal glands. Based on the findings of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), we had considered that the cause of the hyponatremia was syndrome of inappropriate secretion of antidiuretic hormone (SIADH) due to active extrapulmonary tuberculosis. Against our expectations, the patient's condition got worse just after he began antituberculous therapy; we finally diagnosed Addison's disease by additional hormonal tests. His condition recovered immediately with the administration of high-dose hydrocortisone, and the tuberculous lesions became smaller with antituberculous medications. Although tuberculous Addison's disease has been decreasing markedly in recent years, we have to consider the possibility of adrenal insufficiency when hyponatremia is observed in patients with active tuberculosis or those having a past history of tuberculosis.

The present study was designed to elucidate the role of Vgamma4(+) gammadelta T cells, a major subset of pulmonary gammadelta T cells, in host defense against infection with Streptococcus pneumoniae. The proportion and number of whole gammadelta T cells, identified as CD3(+) and TCR-delta(+) cells, and Vgamma4(+) gammadelta T cells, identified as CD3(+) and TCR-Vgamma4(+) cells, increased in the lungs at 3, 6 and 12h post-infection. Survival of infected mice and lung bacterial clearance were severely impaired in TCR-Vgamma4(-/-) mice compared with control wild-type (WT) mice. The impaired host protection in TCR-Vgamma4(-/-) mice correlated well with attenuated recruitment of neutrophils in lungs. MIP-2 and TNF-alpha synthesis in the infected tissues was significantly reduced in TCR-Vgamma4(-/-) mice compared with WT mice. Similar results were noted in the synthesis of TNF-alpha, but not clearly of MIP-2, by lung leukocytes stimulated with live bacteria. Our results demonstrate that Vgamma4(+) gammadelta T cells play an important role in the neutrophil-mediated host defense against S. pneumoniae infection by promoting the synthesis of TNF-alpha and possibly of MIP-2 in the lungs.

Previously, we demonstrated that Valpha14+ NKT cells and IFN-gamma are important upstream components in neutrophil-mediated host defense against infection with Streptococcus pneumoniae. In the present study, we extended these findings by elucidating the role of IFN-gamma in this Valpha14+ NKT cell-promoted process. Administration of recombinant IFN-gamma to Jalpha18KO mice prolonged the shortened survival, promoted the attenuated clearance of bacteria and improved the reduced accumulation of neutrophils and synthesis of MIP-2 and TNF-alpha in the lungs, in comparison to wild-type (WT) mice. In addition, intravenous transfer of liver mononuclear cells (LMNC) from WT mice into Jalpha18KO mice resulted in complete recovery of the depleted responses listed above, whereas such effects were not detected when LMNC were obtained from IFN-gammaKO or Jalpha18KO mice. Activation of Valpha14+ NKT cells by alpha-galactosylceramide (alpha-GalCer) significantly enhanced the clearance of bacteria, accumulation of neutrophils and synthesis of MIP-2 and TNF-alpha in the infected lungs; this effect was significantly inhibited by a neutralizing anti-IFN-gamma antibody. Finally, in a flow cytometric analysis, TNF-alpha synthesis was detected largely by CD11b(bright+) cells in the infected lungs. Our results demonstrated that IFN-gamma plays an important role in the neutrophil-mediated host protective responses against pneumococcal infection promoted by Valpha14+ NKT cells.

CD1d-restricted NKT cells are reported to play a critical role in the host defense to pulmonary infection with Pseudomonas aeruginosa. However, the contribution of a major subset expressing a Valpha14-Jalpha18 gene segment remains unclear. In the present study, we re-evaluated the role of NKT cells in the neutrophilic inflammatory responses and host defense to this infection using mice genetically lacking Jalpha18 or CD1d (Jalpha18KO or CD1dKO mice). These mice cleared the bacteria in lungs at a comparable level to wild-type (WT) mice. There was no significant difference in the local neutrophilic responses, as shown by neutrophil counts and synthesis of MIP-2 and TNF-alpha, in either KO mice from those in WT mice. Administration of alpha-galactosylceramide, a specific activator of Valpha14+ NKT cells, failed to promote the bacterial clearance and neutrophilic responses, although the same treatment increased the synthesis of IFN-gamma, suggesting the involvement of this cytokine downstream of NKT cells. In agreement against this notion, these responses were not further enhanced by administration of recombinant IFN-gamma in the infected Jalpha18KO mice. Our data indicate that NKT cells play a limited role in the development of neutrophilic inflammatory responses and host defense to pulmonary infection with P. aeruginosa.

Interleukin (IL)-12 is a critical cytokine in the T helper (Th)1 response and host defense against intracellular microorganisms, while its role in host resistance to extracellular bacteria remains elusive. In the present study, we elucidated the role of IL-12 in the early-phase host defense against acute pulmonary infection with Streptococcus pneumoniae, a typical extracellular bacterium, using IL-12p40 gene-disrupted (IL-12p40KO) mice. IL-12p40KO mice were highly susceptible to S. pneumoniae infection, as indicated by the shortened survival time, which was completely restored by the replacement therapy with recombinant (r) IL-12, and increased bacterial counts in the lung. In these mice, recruitment of neutrophils in the lung was significantly attenuated when compared to that in wild-type (WT) mice, which correlated well with the reduced production of macrophage inflammatory protein (MIP-2) and tumor necrosis factor (TNF)-alpha in the infected tissues at the early phase of infection. In vitro synthesis of both cytokines by S. pneumoniae-stimulated lung leukocytes was significantly lower in IL-12p40KO mice than in WT mice, and addition of rIL-12 or interferon (IFN)-gamma restored the reduced production of MIP-2 and TNF-alpha in IL-12p40KO mice. Neutralizing anti-IFN-gamma monoclonal antibody (mAb) significantly decreased the effect of rIL-12. Anti-IFN-gamma mAb shortened the survival time of infected mice and reduced the recruitment of neutrophils and production of MIP-2 and TNF-alpha in the lungs. Our results indicated that IL-12p40 plays a critical role in the early-phase host defense against S. pneumoniae infection by promoting the recruitment of neutrophils to the infected tissues.

Interferon (IFN)-gamma plays an essential role in host defense against infection with Mycobacterium tuberculosis, and its synthesis is critically regulated by interleukin (IL)-12, IL-18 and the recently identified IL-23. The present study was designed to determine the roles of these cytokines in IFN-gamma-mediated host defenses against M. tuberculosis. For this purpose, we compared host protective responses in IL-12p40 and IL-18 double-knockout (DKO) mice (which lacked both IL-12/IL-18 and also IL-23) and IFN-gamma gene-disrupted (GKO) mice. DKO mice were more resistant to the infection than GKO mice, as indicated by their extended survival and reduced live colony numbers in spleen, liver and lung. IFN-gamma was detected by ELISA in liver and lung homogenates, but not in spleen and serum, and in all organs by RT-PCR in DKO mice at comparable or reduced levels to those in wild-type mice. IFN-gamma production was reduced by depletion of CD4+ T cells, but not of natural killer (NK), NKT, gammadeltaT and dendritic cells. Neutralization of IFN-gamma or TNF-alpha by specific monoclonal antibodies (mAbs) significantly shortened the survival time of the infected DKO mice. Furthermore, anti-TNF-alpha mAb partially attenuated IFN-gamma synthesis in the liver of these mice. Finally, the expression level of inducible nitric oxide synthase (iNOS) mRNA in the spleen, liver and lung was considerable in DKO mice but only marginal or undetected in GKO mice. Our results indicate the presence of IL-12-, IL-18- and IL-23-independent host protective responses against mycobacterial infection mediated by IFN-gamma, which was secreted from helper T cells.