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Gram positive bacteria have been isolated from water-damaged
building materials. Actinomycetes (Actinobacteria), including several species of Streptomyces, Nocardia and Mycobacterium, were cultured from indoor air and dust as well as from moldy, water-damaged materials (Peltola et al, 2001a, b; Rintala et al, 2001, 2002, 2004; Rautiala et al, 2004; Torvinen et al, 2006). 

Several species of both potentially pathogenic and saprophytic Mycobacteria were isolated from the workplace air during remediation (Rautiala et al, 2004). Some of the identified species belonged to the Mycobacterium avium complex and are potential human pathogens. It was noted by the authors that the mycobacteria are slow growing. 

The Actinomycetes are potential human pathogens. The reporting of these infections in the U.S. is not required; therefore, it is impossible to determine disease prevalence.

Streptomyces californicus produces spores approximately 1 micron in mean aerodynamic diameter that can penetrate deep into alveolar spaces of the lungs. Intrathecal instillation of spores in mice caused inflammation characterized by increase concentrations of TNF alpha, IL6, LDH, albumin, and hemoglobin in bronchoalveolar lavage fluid (BAL) and sera (Jussila et al, 2001).

Moreover, following repeated exposures to the spores in a dose response study, the inflammation was systemic--involving recruitment of neutrophils, macrophages and activated lymphocytes into the airways and decreased numbers of spleen cells. The dose response was nonlinear. 

BAL from the mice also contained increased concentrations of albumin, total protein, LDH and activated lymphocytes. It was concluded that S. californicus spores are capable of causing both lung inflammation and systemic immunotoxic effects (Jussila et al, 2002a, 2003). 

It is interesting that Streptomycetes produce anthracyclines, (e.g., daunorubicin and doxorubicin) drugs widely used in chemotherapy (Arcamone, 1998; Arcamone and Cassinelli, 1998). The anthracyclines cause apoptosis of activated and nonactivated lymphocytes as well as a decrease of mature T and B cells in mice. The T and B cell depletion was most severe in the spleen, moderate in lymph nodes and least in the thymus (Ferraro et al, 2000). 

In addition, various species of this genus are the source for a variety of antibiotics (Gunsalus, 1986). 

The inflammatory and cytotoxic affects in vitro of indoor air bacteria compared to mold spores has been reported. The bacteria tested were Bacillus cereus, Pseudomonas fluorescens, and the molds tested were Streptomyces californicus, A. versicolor, P. spinulosum, and S. chartarum. The bacteria caused the production of IL6 and TNFalpha in mouse macrophages. 

Only the spores of S. californicus caused a production of nitric oxide (NO) and IL6 in both mouse and human cells. Of the molds, only S. chartarum caused the production IL6 in human cells. The overall potency to stimulate the production of proinflammatory mediators decreased in order as follows: Ps. fluorescens, S. californicus, B. cereus, S. chartarum, A. versicolor, P. spinulosum. There was a synergistic response of TNFalpha and IL6 after coexposure with S. californicus with both trichodermin and 7alphahydroxytrichodermol.

These observations indicate that bacteria in water-damaged
buildings should also be considered as causing inflammatory effects on occupants (Huttunen et al, 2004). 

The synergism and interaction of S. californicus and S. chartarum on mouse macrophages have been reported. Spores from these two organisms were tested for the effects on macrophages as follows: spores isolated from co-cultivated cultures, mixture of the spores from separate pure cultures and the spores of each organism. Spores isolated from the co-cultures were compared to the mixture of spores and were more cytotoxic than either the mixture of spores or the spores from each organism. Co-cultured spores caused increased apoptosis of the macrophages by more than 4fold.

Cells arrested at G2/M stage of the cell cycle were increased nearly two-fold. In contrast, the co-cultured spores significantly decreased the ability of the spores to trigger the production of NO and IL-6 by the macrophages. Thus, co-culturing of the two organisms resulted in microbial interactions that significantly potentiated the ability of spores to cause apoptosis and cell cycle arrest (Penttinen, et al, 2005). 

In a follow-up study, the same authors (Penttinen et al, 2006) compared the cytotoxicity of the co-cultured spores (S. californicus and S. chartarum) to that of chemotherapeutics (doxorubicin, phleomycin, actinomycin D and mitomycin C) produced by S. californicus. The co-cultured spores mediated apoptosis, cell cycle arrest at the S-G2/M phase and caused a 4-fold collapse of mitochondrial membrane potential. 

In addition, a 6-fold increase in caspase-3 activation and DNA fragmentation was observed. The cytotoxicity of the co-cultured spores was similar to that caused by doxorubicin and actinomycin D. It was concluded that the co-culture of the two organisms caused the production of unknown cytotoxic compound(s) which evoked immunotoxic effects similar to chemotherapeutic drugs. In conclusion, these studies demonstrate that spores from S. californicus are cytotoxic to mouse macrophages. 

More importantly, the co-cultivation of S. californicus and S. chartarum results in a spore mixture that is more toxic than the spores of each organism cultured individually. 

Additional attention must be paid to the synergism that probably occurs in the microbial mixture that is present in water-damaged buildings. 

Moreover, the spores of S. californicus were more toxic to mouse macrophages than was a mixture of spores from co-cultures with various molds (A. versicolor, P. spinulosum and S. chartarum). S. californicus spores alone were more potent inducers of inflammatory and cytotoxic responses than any combination of co-cultivated spore mixtures. 

In addition, co-culture of S. chartarum and A. versicolor produced a synergistic increase in cytotoxicity with no effect on inflammatory responses of the macrophages (Murtoniemi et al, 2005). 

Finally, S. griseus strains isolated from indoor environments produce a toxin, valinomycin, which causes mitochondrial swelling, damaged mitochondrial membranes and disrupted the mitochondrial membrane potential of boar sperm (Andersson, et al, 1997; Peltola et aI, 2001a). 

The Nocardiopsis strains isolated from indoor water-damaged environments are toxigenic and produce a mitochondrial toxin that damages the mitochondria of boar sperm (Peltola et al, 2001a, b). In conclusion, these studies demonstrate that spores from S. californicus are cytotoxic to mouse macrophages. 

More importantly, the co-cultivation of S. californicus and S. chartarum results in a spore mixture that is more toxic than the spores of either organism cultured individually. Additional attention must be paid to the synergism that probably occurs in the microbial mixture that is present in water-damaged buildings. 

Finally, Nocardia isolated from water-damaged building materials also cause cytotoxicity.

Streptomyces species are associated with farmer's lung disease (allergic alveolitis). Infections (Streptomycosis) occur most frequently in immunocompromised individuals and people with diabetes mellitus and/or corticosteroid therapy. However, co-infection with Aspergillus in cases of chronic granulomatous disease following exposure to aerosolized mulch has been reported (Siddiqui et al, 2007). Diagnosis is difficult because mimicry of other diseases (Kagen et al,1981; Che et al,1989; Roussel et al, 2005; Kapadia et aI, 2007; Kofteridis, et al, 2007; Madhusudhan et aI, 2007; Acevedo et aI, 2008; Quintana et aI, 2008). 

Finally, Streptomyces spp. can cause mycetoma, a condition most endemic around the Tropic of Cancer, but also occurs worldwide, in the U.S., Asia, and Latin America (Welsh et al, 2007; Quintana et al, 2008). The organisms are aerobic, producing chalky aerial mycelia and produce granules of different sizes, textures and colors. Streptomyces do not stain with hematoxylin and eosin, but are gram positive and acid fast stain.
Streptomyces_gram positive

Streptomyces (Gram positive)

Mycobacterium avium complex_gram positive

Mycobacterium avium complex (Gram positive)

Nocardia are aerobic and infectious (Nocardiosis), producing pulmonary disease, skin infections, lymphocutaneous lesions and brain abscesses (Mari et al, 2002; Shook & Rapini, 2006; Bennett et al, 2007). The genus contains approximately 15 known species. 

The species identified in human pulmonary and systemic infections include asteroides, pseudobrasilenisis, otitidis-cavriarum, abscessus, farcinica, nova, transvalensis (Georghiou and Blacklock 1992; Groves; 1997; Yourke and Rouah, 2003; Bennett et al, 2007; Kennedy et al, 2007). 

N. cyriacigeorgica recently was identified as an emerging pathogen in the U.S. and probably worldwide (Schlaberg et al, 2008). 

Lymphocutaneous, subcutaneous mycetoma with sulfur granules and superficial skin infections also occur (Shook and Rapini, 2007). N. asteroides was identified with pneumonia and empyema (thoracis) in a healthy 40-day-old neonate after presumed inhalation exposure (Tantracheewathorn, 2004). 

Nocardia are gram positive and stain partially with acid fast. Serological tests are not available. 

Predisposing factors are immunocompromised individuals, pre-existing lung disease, corticosteroid therapy and diabetes mellitus (Georghiou and Blacklock, 1992; Mari et al, 2001; Bennett et aI, 2007). 

As occurs with Streptomyces, the disease process can exhibit mimicry. Case reports of immunocompetent patients include brain abscesses (Chakrabarti et al, 2008; Kandasamy J et al, 2008; Dias et al, 2008), spinal cord abscess (Samkoff et al, 2008), mimicry of metastatic brain tumor (Kawakami et al, 2008), ventriculitis/choroid plexitis (Mongkolrattanothai et al, 2008), lymphangitis (Dinubile 2008), lung abscesses (Mari et al, 2001; Martinez et al, 2008 Tada et al, 2008), endophthalmitis (Ramakrishnan et al, 2008), and sternal osteomyelitis with mediastinal abscess (Baraboutis et al, 2008). 

It is recommended that 16s rDNA sequencing should be used to identify infections of novel bacteria (Woo et al, 2008).

Mycobacteria are common in moisture-damaged building materials (ceramic, wood and mineral insulation), and their occurrence increases with the degree of mold damage (Rautiala et al, 2004; Torvinen, et al, 2006). They are environmental (soil, water, sewage), opportunistic gram positive bacteria capable of causing hypersensitivity pneumonitis as well as cervical lymphadenitis in children. 

Mycobacteria have been isolated from water systems, spas, hot tubs, and humidifiers and are resistant to disinfection (Primm et al, 2004; Torvinen et al, 2007). The CDC has implicated Mycobacterium avium, terrae and immunogenum in outbreaks of hypersensitivity pneumonitis (Falkinham, 2003a, b). 

M. terrae isolated from the indoor air of a moisture-damaged building induced a biphasic inflammatory response after intrathecal instillation into mouse lungs. There was an initial increase in TNF alpha and IL-6 at 6 hr. to 3 days, followed by a second phase at 7 to 28 days (Jussila et al, 2002a, b). 
The genus Mycobacterium consists of approximately 117 species of which 20 are potential human pathogens. They cause nontuberculous mycobacteria (NTM) lung disease (American Thoracic Society, 2007). 

Mycobacterium avium-intracellulare organisms are increasingly significant pathogens in North America causing a pulmonary infection named MAC (M. avium Complex). M. kansasii, chelonae and fortuitum are other important pathogens (Iseman et aI, 1985; Fujita et aI, 2002; Kuhlann and Woeltje, 2007; Fritz and Woeltje, 2007; Agrawal and Agrawal, 2007). 

According to the American Thoracic Society (2007), "The minimum evaluation for NTM should include the following: 1) Chest radiograph or, in absence of cavitation, chest high-resolution computed tomography (HRCT) scan; 2) Three or more sputum specimens stained for acid-fast bacilli (AFG) analysis; and 3) Exclusion of other disorders such as tuberculosis. Clinical, radiographic and microbiologic criteria are equally important and all must be present to make a diagnosis of NTM lung disease. 

The following criteria apply to symptomatic patients with radiographic opacities, nodular or cavitary, or HRCT scan that shows multifocal bronchiectasis with multiple nodules. These criteria fit best with Mycobacterium avium complex (MAC), M. kansasii, and M. abscessus. There is not enough known about NTM of other species to be certain that these diagnostic criteria are universally applicable to all NTM respiratory pathogens. 

A microbiologic diagnosis includes one of the following: 1) Positive cultures from two separate expectorated samples; 2) Positive culture from at least one bronchial wash; 3) transbronchial or other lung biopsy with mycobacteria histopathologic features. 

Patients suspected of having NTM lung disease but who do not meet the diagnostic criteria should be followed until the diagnosis is firmly established or excluded. NTM is on the rise worldwide. Mycobacteria have been isolated from water-damaged building materials from indoor environments. Finally, individuals treated with corticosteroids are at an increased risk.    
M. ulcerans is a significant human pathogen that causes Buruli ulcer (BU). Cases of BU have been reported worldwide with the greatest burden of disease occurring in West and Central Africa. Its transmission source is not fully understood, but it may be waterborne. The disease is characterized by progressive, severe necrotizing skin lesions that do not respond to antimicrobial therapy and may either require either surgical excision or amputation as treatment. M. ulcerans is an intracellular pathogen. It produces a polyketide-derived macrolide, mycolactone. 

Mycolactone is cytotoxic at 2 ng/ml, and is the organism’s virulence factor. Mycobacterium scrofulaceum and kansasii and other mycobacteria produce a less cytotoxic (33 to 1,000 ug/ml) lipid chemical when tested on fibroblast in vitro (Daniel et al, 2004; Yip et al, 2007). 

The gram positive toxic organisms identified in indoor environments also include Bacillus spp, Nocardia spp. and Streptomyces spp. (Peltola et al, 2001a,b). Mycobacteria have been isolated from damp indoor environments (Jusilla et al, 2001, 2002a; Falkinham, 2003a, b). 

Examples of additional gram positive bacteria are species of Atrhrobacter, Bacillus, Cellumonas, Gordona, and Paeniibacillus (Andersson et al, 1997). Bacillus simplex and Amyloliquefaciens isolated from moisture-damaged buildings produce surfactin (Iipopeptide) and peptides that adversely affect cell membranes and mitochondria (Mikkola et al, 2004, 2007). 

Finally, there were elevated concentrations of Staphylococci and Actinomycetes in a water-damaged home in which a 3-month-old infant died from a Reye's-like syndrome with mitochondrial damage resulting in decreased enzymatic activity of complexes I-IV. Mitochondrial DNA mutation testing of the infant resulted in negative findings for known mitochondrial diseases. This home also contained several species of Aspergillus, Penicillium and S. chartarum (Gray et al, in preparation).

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