<p>Gliotoxin contributes to the virulence of the fungus <i>Aspergillus fumigatus</i> in non-neutropenic mice that are immunosuppressed with corticosteroids. To investigate how the absence of gliotoxin affects both the fungus and the host, we used a nanoString nCounter to analyze their transcriptional responses during pulmonary infection of a non-neutropenic host with a gliotoxin-deficient Δ<i>gliP</i> mutant. We found that the Δ<i>gliP</i> mutation led to increased expression of <i>aspf1</i>, which specifies a secreted ribotoxin. Prior studies have shown that <i>aspf1</i>, like <i>gliP</i>, is not required for virulence in a neutropenic infection model, but its role in a non-neutropenic infection model has not been fully investigated. To investigate the functional significance of this up-regulation of <i>aspf1</i>, a Δ<i>aspf1</i> single mutant and a Δ<i>aspf1</i> Δ<i>gliP</i> double mutant were constructed. Both Δ<i>aspf1</i> and Δ<i>gliP</i> single mutants had reduced lethality in non-neutropenic mice, and a Δ<i>aspf1</i> Δ<i>gliP</i> double mutant had a greater reduction in lethality than either single mutant. Analysis of mice infected with these mutants indicated that the presence of <i>gliP</i> is associated with massive apoptosis of leukocytes at the foci of infection and inhibition of chemokine production. Also, the combination of <i>gliP</i> and <i>aspf1</i> is associated with suppression of CXCL1 chemokine expression. Thus, <i>aspf1</i> contributes to <i>A. fumigatus</i> pathogenicity in non-neutropenic mice and its up-regulation in the Δ<i>gliP</i> mutant may partially compensate for the absence of gliotoxin.</p> <p><b>Abbreviations</b>:PAS: periodic acid-Schiff; PBS: phosphate buffered saline; ROS: reactive oxygen species; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling</p
